Spinal Surgery News

Issue 17 Spring 2010

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SpinalSurgeryNews spinalsurgerynews.com

UK ÂŁ6.00

Spring 2010

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Spinal Surgery News - Spring 2010

CONTENTS

EDITORIAL

04 NEWS All the latest Spinal Surgery news

12 TRADE TOOLS

04 NEWS

Taking a look at new and current products

16 MEETINGS A comprehensive guide to what’s on

22 FEATURE ARTICLE

12 TRADE TOOLS

Pyogenic Spondylodiscitis

26 ARTICLE Expression of cartilage-derived morphogenetic protein in human intervertebral discs and its effect on matrix synthesis in degenerate human nucleus pulposus cells

22 FEATURE ARTICLE

In The Next Issue...

warm welcome to the Spring 2010 issue of SSN. Our magazine is now four years old where does the time go? I certainly remember working on the very first issue back back in the winter of 2005 and I am proud how much SSN has grown since then, with new contributors, clients and readers alike. I hope you will continue to pick up this journal, and please do keep your comments, submissions and news coming in.

In the news we have a story on the National Patient Safety Agency (NPSA) launching a campaign to promote the use of safer spinal and epidural devices throughout healthcare organisations across the UK. It is hoped this initiative will help further minimise the risk of potentially fatal consequences from wrong route errors.

Along with our news, future events and updated Trade Tools section, we also have articles on pyogenic spondylodiscitis, and the application of morphogenetic protein to treat degenerated intervertebral discs, a major cause of back pain. Enjoy the issue.

A

Summer 2010

Matt Ng Editor

Reconstructive Spinal Surgery & Micro-Discectomy

Group Editor.........................Les Charneca - les@spinalsurgerynews.com Editor............................................Matt Ng - matt@spinalsurgerynews.com Deputy Assistant Editor.......Kate Jackson - kate@spinalsurgerynews.com Design................................Neil Molyneaux - neil@spinalsurgerynews.com Group Sales Manager........Debbie Hall - debbie@spinalsurgerynews.com Accounts..............................Gaye Wright - gaye@spinalsurgerynews.com New Media.....................................................................................Andy Hill IT Support..............................................................................Matt Wensley Proof Reading...........................................................................Colin Taylor Design Consultant............................................................Sarah Charneca Consultant Editor...................................................................Sashin Ahuja Spinal Surgery News is available on subscription: £24.00 U.K. £32.00 Europe (Airmail) £42.00 elsewhere (Airmail) Published in the UK by: Pelican Magazines Ltd Address: 2 Cheltenham Mount, Harrogate HG1 1DL, England Tel: +44 (0)1423 569676 Fax: +44 (0)1423 569677 Web Site: www.spinalsurgerynews.com Every effort is made to ensure that information given in this magazine is accurate but no legal responsibility is accepted by the Editor or Publisher for errors or omissions in that information. Readers are recommended to contact manufacturers direct. Views expressed by contributors are not necessarily shared by Spinal Surgery News. Printed in the UK by Buxton Press.

Copyright © 2010 Pelican Magazines Ltd.

We welcome reader comments and letters Send them to the address above

Cover Feature: Zimmer Spine Zimmer Spine EMEA, headquartered in Bordeaux (France), develops, produces and markets the highest quality spine products and services that repair, replace and regenerate spine health.

Zimmer Spine’s comprehensive and growing portfolio includes state-of-the-art technologies for Thoracolumbar and Cervical pathologies.

In Thoracolumbar Fusion, Zimmer Spine offers the latest spinal fixation systems, Sequoia®, and other innovative solutions including the Universal Clamp® implant. Additionally, Zimmer Spine proposes a full range of Trabecular Metal cages, a unique highly porous material designed to replicate the shape, structure, elasticity and weight bearing characteristics of bone.

Zimmer Spine also has a leading presence in Dynamic Stabilization with the Dynesys® system and the Wallis® Implant, these two devices combining 38 years of clinical experience with over 75,000 surgeries performed worldwide.

Zimmer Spine EMEA 23 parvis des Chartrons 33080 Bordeaux France Tel: +33 556 001 820 Fax: +33 556 001 821 Web: www.zimmerspine.eu

Email us: editor@spinalsurgerynews.com

Stay up-to-date: be sure to visit our brand new website: www.spinalsurgerynews.com Spring 2010

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NEWS

Introduction of safer spinal and epidural devices will reduce risk of wrong route errors, say NPSA The National Patient Safety Agency (NPSA) has announced an initiative that will see the NHS and healthcare industries develop safety design solutions which will improve patient safety.

The NPSA’s latest Patient Safety Alert advises all NHS organisations across England and Wales to introduce purchasing for safety initiatives to eliminate the use of luer universal connectors and intravenous infusion spikes in spinal (intrathecal), epidural and regional devices, which they say should further minimise the risk of wrong route errors.

NHS organisations are being asked to ensure that all spinal (intrathecal) bolus doses and lumbar puncture samples are only performed using syringes, needles and other devices with connectors that will not also connect with intravenous luer connectors. The deadline for compliance to this Patient Safety Alert is April 2011.

The Patient Safety Alert also stresses the need for all epidural, spinal (intrathecal) and regional anaesthesia infusions and bolus doses to be performed with devices with safer connectors that will not connect with intravenous luer connectors and intravenous infusion spikes by April 2013.

Welcoming the announcement, Chief Medical Officer for England, Sir Liam Donaldson said: “Wrong route medication administration incidents are rare events, but they have occurred with utterly tragic and fatal consequences.

“Several years ago we recognised that these events could only be eliminated through engineering different devices involved in administering such medicines to ensure they cannot be inadvertently connected the wrong way. Error cannot be eliminated just by imploring people to take more care.

“It has taken considerable persistence to devise and test suitable connectors. We were told that there was no market worldwide. We were not prepared to accept this and remained determined to find a solution that would reduce risk to patients. We are now at the point of setting out a clear timetable for when the NHS will only purchase this intrinsically safer technology.

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“Although it has been a long road, I am pleased, at last, for the families of those who have suffered from these events that we are today able to give a firm commitment on how they will be prevented in the future.”

The NPSA’s Medical Director, Dr Kevin Cleary, said: “Luer connectors are used thousands of times each day by NHS clinicians without any complications or problems. This Patient Safety Alert will further reduce any chance of wrong route errors which can lead to patient harm. This will make safe care even safer.

“The NHS will become the first healthcare system in the world to implement medical devices with safer designs for spinal, epidural and regional anaesthesia use.”

NPSA’s Head of Safe Medication Practice, Professor David Cousins, said: “Devices with safer connectors are not currently available. By issuing this alert the NHS is stating clearly to medical device manufacturers and the pharmaceutical industry that it will only buy products that facilitate safe practice in the future.

“The timescales within the alert give NHS organisations adequate time to ensure they have systems in place to introduce the devices with safer connectors by the specified deadline.”

In the past, there have been fatal cases where intravenous medicines have been administered by the spinal (intrathecal) route and epidural medicines have been administered by the intravenous (vein) route.

The last reported fatal wrong route incident involving epidural medicine was in February 2007. There have been no further reports of intravenous vincristine being administered by the spinal route in the UK, but additional deaths have occurred in other countries.

In addition, there have been 18 low or no harm incidents reported to the NPSA between 1 January 2008 and 31 July 2009, where misconnection errors have occurred. This has meant drugs intended for one route of administration (for example, spinal or epidural) have been administered via an inappropriate route.

Professor Ravi Mahajan, Chairman of

the Royal College of Anaesthetists’ Safe Anaesthesia Liaison Group, said: “This is an excellent example of the NPSA and professional bodies working together to improve the existing systems to minimise risks from wrong route errors in patients requiring drug administration for spinal, epidural or regional anaesthesia/ analgesia. The implementation of this Alert, no doubt, will significantly improve patient safety in clinical practice.”

Since 2001, the NPSA has been working with healthcare organisations and manufacturers to ensure that safety changes are made in the design of medical devices used to administer medicines for spinal, epidural and regional anaesthesia procedures.

Professor Cousins added: “Manufacturers are fully aware of the NHS’ new purchasing for safety requirements. They have indicated that they are striving to respond to these requirements within the identified timescales.”

The NPSA has previously issued guidance to minimise the risks of wrong route epidural incidents, and the Department of Health has issued guidance on intrathecal chemotherapy.

The introduction of devices with safer connectors does not replace this guidance, but is intended to further reduce risk of wrong route errors.

Professor Mike Richards from the Cancer Network in England said: “I welcome the steps being taken by the National Patient Safety Agency and industry to develop safer systems for delivering spinal injections. These will reduce even further the risk of patients receiving drugs by the wrong route, which can have fatal consequences.”

Dr Andrew Hartle, Chairman of the Association of Anaesthetists’ Safety Committee, said: “Now that this Patient Safety Alert has been issued, anaesthetists should engage with local processes to make sure this is a priority for their organisation. Clinical engagement is vital if we are to avoid being forced to accept products that either do not work or are less easy to use than the current equipment.”

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NEWS

US research shows modified adult stem cells may be helpful in spinal cord injury Researchers at UTHealth in Texas, US have demonstrated in rats that transplanting genetically modified adult stem cells into an injured spinal cord can help restore the electrical pathways associated with movement. The study’s results are published in a recent issue of the Journal of Neuroscience.

The research team, led by Qilin Cao, M.D., principal investigator and associate professor of neurosurgery at UTHealth (The University of Texas Health Science Center at Houston), discovered that transplanted adult stem cells (oligodendrocyte precursor cells or OPC) from the spinal cord could become oligodendrocytes. The new cells helped restore electrical pathways of the spinal cord and therefore, function, in a process called remyelination.

Cao said two important discoveries were isolating precursor cells from the adult spinal cord and, prior to transplanting them into the spinal cord, genetically modifying them to express ciliary neurotrophic factor (CNTF), a protein that encourages nerve growth. In preliminary experiments, also published in this paper, CNTF was shown to facilitate survival and differentiation of OPCs in cell culture.

“Most importantly, the evidence of remyelination was shown to exactly coincide with the anatomical localisation of these motor pathways in spinal cord white matter,” Cao said. “These latter data provide confidence that the mechanism by which the grafted OPCs are enhancing functional recovery is through remyelination.”

Previous studies by the team and other researchers have shown that grafted OPCs survive after grafting into an injured spinal cord and increase movement recovery, but the mechanical connection to remyelination had only been theorised. In this research, results showed that there was significantly enhanced behavioral recovery, return of electrophysiological conduction and ultra-structural evidence of remyelination.

The clinical significance is two-fold, Cao said: “First it confirms what has been suggested by these and other authors that stem cell grafting in attempts to remyelinate an injured spinal cord is a viable therapeutic strategy. Secondly, it strongly cautions that optimal recovery using such an approach will require more than simply grafting naïve precursor cells.”

Medtronic donates medical supplies to Haiti relief effort Medtronic, Inc. has announced that the company has donated nearly $900,000 in medical devices and surgical supplies to help meet urgent medical needs in Haiti.

In response to numerous spine and crush injuries, the company provided spinal surgical implants such as rods, hooks and screws to treat spinal fractures, facilitate spinal fusion and stabilise and strengthen the spine. Spinal orthopaedic implants and replacement devices were provided for trauma reconstruction. Additionally, surgical perfusion disposables such as tubing, and blood and oxygen filters were donated for field and hospital use. All products were identified as high-need by several agencies working directly with medical relief efforts.

Medtronic is partnering with U.S.based Hospital Sisters Mission Outreach to coordinate distribution of the donated medical devices, and encourages medical professionals and aid organisations requesting product donations to contact that organisation directly. Contact information is available on the home page of www.medtronic.com.

Combined with $1.2 million in cash pledges, the announcement raises Medtronic’s total response to more than $2.1 million.

The $1.2 million includes $750,000 in Medtronic Foundation grants directed to the rebuilding of healthcare infrastructure in Haiti, and the Foundation will match employee donations up to $350,000 (increased from a previously announced $250,000 match due to strong employee response). An additional $100,000 was given to several relief organisations in the Minneapolis/Saint Paul area. Matching

funds will be directed to Partners in Health for short-term relief. The Foundation is assessing potential nonprofit partners to lead the longer-term rebuilding efforts. Employees worldwide also are offered five days of paid leave to assist in recovery efforts.

These donations are in addition to an existing five-year, $500,000 grant to the International Federation of Red Cross and Red Crescent Societies disaster relief fund, which ensures that immediate financial support is available for responding to emergencies around the globe.

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NEWS

US survey finds many surgeons suffer injuries from minimally invasive techniques Surgeons who engage in minimally invasive, laparoscopic surgery are providing great benefits to their patients, but possibly to their own detriment, according to findings from a survey from surgeons in North America.

The survey, developed at the University of Maryland School of Medicine in Baltimore, found that 87 percent of laparoscopic surgeons have experienced physical symptoms or discomfort. This was especially true among those with high case volumes.

Previous surveys had found only a 20-30 percent incidence of occupational injury among these surgeons. Results of the survey appeared in the March 2010 Journal of the American College of Surgeons.

Millions of patients around the world have benefited from minimally invasive surgical techniques introduced some 20 years ago. The benefits include increased safety, quicker recovery, shorter hospital stays and cosmetic advantages compared to open surgery techniques.

Despite these successes, the impact of minimally invasive techniques on those who perform them is little-known and under-appreciated. “We face a pending epidemic of occupational injuries to surgeons and we can no longer ignore their safety and health,” says the survey’s principal author, Adrian E. Park, M.D., chief of general surgery at the University of Maryland Medical Center and professor of surgery and vice chair of the Department of Surgery at the University of Maryland School of Medicine.

“Sadly, it is easier for a surgeon to obtain an ergonomic assessment and direction to improve his golf swing than his posture or movement during surgery,” says Dr. Park, who is also executive director of the Maryland Advanced Simulation, Training, Research, and Innovation (MASTRI) Center at the University of Maryland Medical Center. It is the first facility in the world to focus on surgical movement. “If injuries among surgeons are not addressed significantly, we’re going to face a problem in the near future of a shortage of surgeons as well as shortened career longevity among surgeons who enter, or are already in, the field.”

Dr. Park says surgeons who perform

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laparoscopic surgery face constraints that are not part of open surgery. “In laparoscopic surgery, we are very limited in our degrees of movement, but in open surgery we have a big incision, we put our hands in, we’re directly connected with the target anatomy.

With laparoscopic surgery, we operate by looking at a video screen, often keeping our neck and posture in an awkward position for hours,” says Dr. Park. “Also, we’re standing for extended periods of time with our shoulders up and our arms out, holding and maneuvering long instruments through tiny, fixed ports.”

A comprehensive 23-question survey was sent to 2,000 board-certified gastrointestinal and endoscopic surgeons in North America and abroad who are members of the Society of American Gastrointestinal and Endoscopic Surgeons, a diverse group of experienced laparoscopic practitioners. The questions were grouped in four categories: demographics, physical symptoms, ergonomics and environment or equipment.

Some questions required single answers, such as “Have you ever had any physical discomfort or symptoms you would attribute to your laparoscopic operating? Yes/No.” Other questions allowed selection of multiple applicable answers.

Of 317 surgeons completing the survey, 272 (86.9 percent) reported experiencing physical discomfort or symptoms they attributed to performing minimally invasive surgery. The discomfort ranged from eyestrain to problems in the surgeon’s dominant hand, to neck, back and leg pain. A few surgeons also reported headaches, finger calluses, disc problems, shoulder muscle spasm and carpel tunnel syndrome. Age played a role in hand problems, with younger surgeons and those over 60 at highest risk, but there was no correlation between age and symptoms in other parts of the body.

Annual case volume emerged as a key predictor of physical symptoms. Case volume impact was seen in surgeons who had received postgraduate surgical fellowship training. Those surgeons averaged 249 cases a year, while the non-fellowship average was 192. Neck, hand and leg symptoms rose with increased case volume. “If surgeons had more than 150-200 cases a year, they

were at a much higher risk,” says Dr. Park.

“However, if the surgeon did long, complex cases, they only needed half that number to increase the risk.”

To minimise the problems, 84 percent said they had changed their position, while 30 percent said they changed instruments or took a break. Significantly, 40 percent of all participants said they would just ignore any such problem.

Instrument design was listed as the main source of symptoms for more than 74 percent of the surgeons, while 40 percent cited operating room table setup and display monitor location. More than half of the surgeons (58.7 percent) said they were only slightly aware or not aware at all of recommendations to reduce symptoms from researchers in the field of surgical ergonomics.

Dr. Park says the survey results provide important pieces to the puzzle, but ergonomic researchers do not know what all the issues are. As a first step toward developing solutions, he calls for a fresh, comprehensive attempt to understand the surgical workplace. “Many manufacturers and industries have been able to optimise workflow, worker safety and efficiency by characterising their workspace, while we in surgery have done nothing. We have not seriously investigated or addressed the surgeonpatient interface and the surgeon-instrumentation interface. If you go into the cockpit of an airplane, everything is integrated. In the operating room there is very limited integration of technologies,” says Dr. Park.

“The patient has always been the main focus of medicine, as caregivers and researchers grapple with disease treatment and prevention, enhanced patient safety and comfort and the extension of care to more people,” says E. Albert Reece, M.D., Ph.D., M.B.A., vice president for medical affairs at the University of Maryland and dean of the University of Maryland School of Medicine.

“At a time when minimally invasive, laparoscopic techniques are expanding, Dr. Park’s research raises new questions that may affect patient care in the future. It is my hope that further research will provide answers, and will help stem what may indeed be an impending epidemic among surgeons.”

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NEWS

US study finds little effect of soy isoflavones on bone loss in postmenopausal women A previous six-month study by US researchers had indicated that consuming modest amounts of soy protein, rich in isoflavones, lessened lumbar spine bone loss in midlife, perimenopausal women. But now an expanded three-year study by some of those same researchers at Iowa State University does not show a bone-sparing effect in postmenopausal women who ingested soy isoflavone tablets, except for a modest effect at the femoral (hip) neck among those who took the highest dosage.

The multi-centre clinical trial of 224 postmenopausal women -- led by D. Lee Alekel, professor of nutrition and interim associate director of the Nutrition and Wellness Research Center (NWRC) at Iowa State, and supported by the National Institute of Arthritis, Musculoskeletal and Skin Diseases, one of the research institutes of the National Institutes of Health (NIH) - was the longest ever conducted on the effects of soy isoflavones on bone mineral density (BMD). It compared the effects of either ingesting daily 80-mg daily or 120-mg soy isoflavone tablets, compared to placebo tablets on BMD and other health outcomes.

Iowa State NWRC researchers collaborated with research physiologist Marta D. Van Loan and her colleagues at the USDA Agricultural Research Service’s Western Human Nutrition Research Center, located at the University of California, Davis. The

primary results of their study were published in the January issue of The American Journal of Clinical Nutrition.

“Our six-month preliminary study, published in 2000, indicated that soy protein, rich in isoflavones, exerted the greatest impact in slowing the loss of bone mineral density in the lumbar spine,” Alekel said.

“But we believed that we needed to replicate these results in a study with a greater sample size and longer duration, which is what we did with this three-year intervention.

“In this longer study, we had sufficient power to detect change,” she continued.

“We monitored adverse events, had excellent compliance throughout, and accounted for potential confounding factors.”

NWRC research staff members Laura Hanson, Jeanne Stewart and Kathy Hanson also joined Kenneth Koehler and C. Ted Peterson from statistics as part of the eight-member ISU team that conducted the research.

The researchers ran statistical analyses to determine change in BMD at the lumbar spine, total proximal femur (hip), femoral neck and whole body. They accounted for treatment, age, whole body fat mass and bone removal (using a biochemical marker).

While the 120-mg dose soy isoflavones did reveal a small protective effect on femoral neck bone BMD, researchers found no significant effect of treatment on lumbar

spine, total hip, or whole-body BMD. “This trial used isoflavones extracted from soy protein, compressed into tablet form, consumed over the course of three years, which is very different than either providing soy protein or soy foods,” Alekel said. “In our recent study, we did not demonstrate an important biological effect on BMD or bone turnover.”

The new study calls into question the value of postmenopausal women consuming soy isoflavone tablets to help lessen bone loss and minimise the effect of osteoporosis.

“The preponderance of studies that have been published -- particularly the longer term, more carefully conducted studies, like our own -- have shown little to no biological effects of soy isoflavones on BMD,” she said.

“This field of research has attracted ‘believers,’ making it difficult to convince them otherwise. They may continue to believe what they want to believe, rather than what the evidence shows.”

And when it comes to minimising the consequences of osteoporosis in postmenopausal women, Alekel urges a more holistic approach.

“People, in general, would like an easy fix. We would all like soy isoflavones to be that magic pill, but this study has found that they are not,” she said.

3D cinema for the human spine A new method developed by researchers within the framework of the National Research Programme “Musculoskeletal Health – Chronic Pain” (NRP 53) provides a three-dimensional view of spine movements. The researchers hope this will facilitate the development of new artificial disc replacements.

Stephen Ferguson and his team from the Institute for Surgical Technologies and Biomechanics at the University of Bern have now developed a method of reproducing spinal movements in three-dimensional form. The principle: a video x-ray machine, with which many clinics are equipped, films the spine while a patient performs pre-

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scribed movements. A unique new image processing procedure then converts this data into a 3D motion model. The entire procedure is more or less run in real time – producing results that until now have only been obtained by painful, seldom used methods in which probes were implanted on the vertebrae under the skin.

The researchers aim to develop a database for spinal movements. “Pictures of healthy people and patients might help distinguish between normal and abnormal spinal movements”, comments Stephen Ferguson. This, in turn, would facilitate the development of new implants like artificial disc replacements.

However, the method must first become established in practice. For there is still one problem to be tackled: instead of xrays, doctors are increasingly basing their spinal diagnoses on magnetic resonance imaging. Although this technique offers less radiation exposure, it does not image bones so precisely.

The researchers are now working to adapt their method so that magnetic resonance data can also be used. Ferguson views their chances of success optimistically – thus making the method more attractive to partners in industry.

Source: www.snf.ch

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NEWS

Stem cells rescue nerve cells by direct contact Scientists at the Swedish medical university Karolinska Institutet have shown how transplanted stem cells can connect with and rescue threatened neurons and brain tissue.

The results point the way to new possible treatments for brain damage and neurodegenerative diseases.

A possible strategy for treating neurodegenerative diseases is to transplant stem cells into the brain that prevent existing nerve cells from dying. The method has proved successful in different models, but the mechanisms behind it are still unknown. According to one hypothesis, the stem cells mature into fully-mature neurons that communicate with the threatened brain tissue; according to another, the stem cells secrete various growth factors that affect the host neurons.

The new report, co-authored by several international research groups and lead by Karolinska Institutet, shows that stem cells transplanted into damaged or threatened nerve tissue quickly establish direct channels, called gap junctions, to the nerve cells.

Stem cells actively bring diseased neurons back from the brink via cross-talk through gap junctions, the connections between cells that allow molecular signals to pass back and forth.

The study found that the nerve cells were prevented from dying only when these gap junctions were formed.

The results were obtained from mice and human stem cells in cultivated brain tissue, and from a series of rodent models for human neurodegenerative diseases and acute brain injuries.

“Many different molecules can be transported through gap junctions,” says Eric Herlenius, who led the study. “This means that a new door to the possible future treatment of neuronal damage has been opened, both figuratively and literally.”

US hospital set to research nanotechnology in orthopaedic & spine surgery A new research program at a US hospital has become one of the first institutes dedicated solely to advancing nanotechnology in orthopaedics and spine surgery.

Dr. Bradley Weiner, chief of spinal surgery at the Methodist Hospital in Houston, is the director of the Spine Advanced Technology Laboratory (SATL).

He commented: “The use of nanotechnologies to treat disease or repair damaged tissues might allow physicians to intervene more efficiently and safely than currently possible.”

Researchers in the lab will be looking at various ways nanotechnology can improve the treatment of musculoskeletal disease.

“Using nanotechnology, we hope to be able to deliver drugs directly to the affected area thereby limiting exposure to other tissues. In the future, we hope to give an injection into the vein and, with sophisticated mapping, send it directly to specific musculoskeletal tissues, including the spine, and release the medication exactly where it is needed,” Weiner said.

“We are exploring many avenues of intervention such as the delivery of proteins to help bone formation when doing fusions and ways of delivering anti-inflammatory drugs and pain medications to help decrease musculoskeletal pain.”

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Spinal cement may provide real support for cancer patients, suggests study New technologies used to repair spinal fractures could soon be helping patients suffering from the bone marrow cancer multiple myeloma.

A research project led by engineers at the University of Leeds will focus on the disease – an incurable cancer of the bone marrow that causes destructive lesions in bones and makes them more susceptible to fracture.

The study will analyse whether techniques such as injecting cements into the spine to stabilise the bone, or using plates to fix fractures can be adapted for affected patients. Although incurable, improvements in treatment mean that patients with multiple myeloma are surviving for longer, with up to a third surviving for at least five years.

However, a better prognosis means that secondary symptoms, such as painful bone deterioration, have more time to take effect.

“Our aim is to give people suffering from this disease a better quality of life. If the spine becomes weakened or fractures, patients can do little more than stay in bed and try to deal with the pain,” said Professor of Spinal Biomechanics, Richard Hall, who is leading the research at Leeds’ Faculty of Engineering. “The majority of multiple myeloma patients are in their sixties or older, but even simple things that we

take for granted, such as sitting your grandchild on your knee, can become impossible for them.”

The work will combine laboratory experiments with computer modelling to predict the impacts of various treatments on patients.

Professor Hall will be collaborating with researchers at the Sunnybrook Health Sciences Centre, housed at one of Canada’s largest hospitals in Toronto, and clinicians from Leeds Teaching Hospitals NHS Trust.

The project team includes Mr Jake Timothy, Consultant Neurosurgeon in Leeds, who has developed an award winning clinical vertebroplasty and kyphoplasty service that can help to fix painful vertebrae and spinal compression fractures associated with osteoporosis. He has seen the dramatic improvement that such procedures can have on the pain scores of patients affected by vertebral myeloma.

“There is still so much unknown about the positive and negative effects of these procedures,” he says. “This money will undoubtedly aid our understanding and help us select which patients will benefit the most from these procedures, improving their quality of life even further.”

Vertebroplasty for patients with osteoporosis provides effective pain relief Patient selection is key for vertebroplasty to be effective and successful, according to a study of more than 1,500 persons who were followed over seven years.

Additionally, collaboration between an interventional radiologist and other medical experts in treating a patient is imperative, say researchers at the Society of Interventional Radiology’s 35th Annual Scientific Meeting in Tampa, USA. “Vertebroplasty puts lives and vertebrae back together,” said Giovanni C. Anselmetti, M.D., interventional radiologist at the Institute for Cancer Research and Treatment in Turin, Italy. “Our longterm follow-up confirmed this: pain relief

and quality of life significantly improved with vertebroplasty,” said Anselmetti.

Anselmetti illustrated a typical case: an 80-year-old Italian woman, who was diagnosed last year with two painful osteoporotic vertebral collapses, underwent medical treatment for osteoporosis (with the drug teriparatide) and was still in pain when she was prescribed an external brace. After there was evidence of two new fractures (verified by MR imaging), she received vertebroplasty, experiencing “complete pain regression, no need for the brace and a dramatic Lazarus-like ability to perform daily activities,” he noted.

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NEWS

Smooth and integrated movement patterns can help individuals with back pain Many people with back pain do not know what is causing it and they do not receive effective treatment, but learning to move in a more integrated way makes a big difference, reveals research from the Sahlgrenska Academy at the University of Gothenburg, Sweden.

“People with long-term back pain often protect themselves by unconsciously limiting their movements,” says physiotherapist Christina Schön-Ohlsson.

“Such inefficient movement patterns gradually become habituated even though the original injury or strain is no longer present.”

The answer to the problem is sensory motor learning, where patients are guided to find out how they are moving and how they can free themselves from selfimposed limitations. This process leads patients to develop their bodily awareness and to trust in their bodily sensations again.

In one of the studies 40 patients were randomly divided into two groups to compare experiences of two different types of

treatment: exercise therapy and sensory motor learning.

“The patients in the sensory motor learning group said that they had learned to trust in themselves and now felt able to handle their low back pain themselves without seeking further medical help,” says Schön-Ohlsson.

This contrasted with the patients in the exercise group, who expressed insecurity and felt dependent on advice from backpain experts.

The overall purpose of the thesis was to evaluate how sensory motor learning, which has its roots in the Feldenkrais method, affected patients with long-term back pain who had previously not been helped by any treatment. The patients’ subjectively experienced positive physical and psychological changes coincided with objectively assessed improvements in movement capacity.

Schön-Ohlsson draws the conclusion that sensory motor learning helps patients to learn to listen

to their body so that they can take care of their back problems themselves.

Scientists shed new light on walking Researchers at the medical university Karolinska Institutet in Sweden have created a genetically modified mouse in which certain neurons can be activated by blue light.

Shining blue light on brainstems or spinal cords isolated from these mice produces walking-like motor activity. The findings, which are published in the scientific journal Nature Neuroscience, are of potential significance to the recovery of walking after spinal cord injury.

“This new mouse model will impact the way in which future studies examining the organisation of neurons involved in walking are performed. We hope that our findings can provide insight that eventually will contribute to treatments for spinal cord injured patients”, says Professor Ole Kiehn, who led the study.

Excitatory neurons have been suggested to play an important role for the initiation and maintenance of locomotion, or walking.

However, this has not been demonstrated directly. In order to test the hypothesis that activation of excitatory neurons is essential to locomotion, a research team at the Department of Neuroscience, Karolinska Institutet, created a genetically modified mouse which expresses a light sensitive protein in excitatory neurons.

The light sensitive protein, Channelrhodopsin2 (ChR2), is normally found in algae and activates the cell it is expressed in when exposed to blue light.

ChR2 has previously been introduced into rodent cells by viral infection, but this can be problematic due to exposure and replication demands. The researchers circumvented the problems by creating the first genetically modified mouse to successfully express ChR2 in a specific set of neurons.

By inserting ChR2 into nerve cells expressing Vglut2 - a transporter found in most excitatory neurons in the brainstem

and spinal cord as well as many excitatory neurons in other regions of the brain they created a Vglut2-ChR2 mouse. The reason for doing this was to be able to selectively activate excitatory neurons in specific regions of the brainstem and spinal cord, as the excitatory neurons are believed to be important for initiating locomotion, or walking.

The researchers then recorded from motor nerves leaving the spinal cord. When blue light was shined directly on the spinal cord, walking-like activity began and was maintained for the duration of the light pulse. This proved that activation of Vglut2expressing excitatory neurons in the spinal cord is sufficient for walking. Walking-like activity could also be initiated by exposing the lower brainstem to blue light, demonstrating that excitatory cells in the brainstem provide a sufficient ‘go’ signal to the spinal neurons involved in walking.

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TRADE TOOLS The Trade Tools section aims to keep the Spinal professional informed of new and current products on the market. To include your product in Trade Tools, please email editor@spinalsurgerynews.com

NuNec ® Cervical Arthroplasty System

SmartCage Expandable Controllable TLIF Cage Dedicated to the Transforaminal Approach It minimises dural exposure, reduces iatrogenic neurologic lesion risks due to excessive root traction and avoids dissection of epidural scar during revision surgeries.

Unique Expansion Feature Ease cage insertion even in severely collapsed disc spaces and asymmetric discopathy. Avoid subsidence risk inside endplates during progression.

Anatomic Biconvex Shape Perfectly adapted to the natural disc space, provides ample contacting surfaces and restores natural lordosis.

With the introduction of the P3™ (Pioneer PEEK-on-PEEK) line, Pioneer™ has exceeded in innovative motion preserving devices with the NuBac™, BacJac™ and NuNec ® systems.

Pioneer’s P3 motion preservation products offer excellent wear resistance, established biocompatibility, biodurability and radiolucency.

The P3 line has been extended with the introduction of the NuNec Cervical Arthroplasty System, the next generation of cervical Total Disc Replacement (TDR). The NuNec features a unique cam locking mechanism which provides optimum fixation without keel cutting as well as an HA coating on the outer surfaces of the PEEK plates to facilitate consistent fixation.

Unlike many cervical disc devices, the radiolucency of the PEEK material in NuNec causes no artifact in MRI or CT imaging.

UK Distributor: Lindare Medical Tel: +44 (0)1233 770370 Fax: +44 (0)1233 770370 Email: customerservices@lindaremedical.co.uk Web: www.lindaremedical.co.uk

Pioneer Surgical Technology BV Tel: +31 30 693 47 20 Fax: +31 30 693 47 21 Web: www.pioneersurgical.eu Email: info@pioneersurgical.eu

Cover Feature: Zimmer Spine Zimmer Spine EMEA, headquartered in Bordeaux (France), develops, produces and markets the highest quality spine products and services that repair, replace and regenerate spine health.

Zimmer Spine’s comprehensive and growing portfolio includes stateof-the-art technologies for Thoracolumbar and Cervical pathologies.

In Thoracolumbar Fusion, Zimmer Spine offers the latest spinal fixation systems, Sequoia®, and other innovative solutions including the Universal Clamp® implant. Additionally, Zimmer Spine proposes a full range of Trabecular Metal cages, a unique highly porous material designed to replicate the shape, structure, elasticity and weight

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Optimum Fusion Conditions Bone graft is transferred to the opposed lateral space.

Additional bone graft material is inserted through the lateral window and all around the cage to entirely fill the disc space and ensure optimal fusion conditions.

Spring 2010

bearing characteristics of bone.

Zimmer Spine also has a leading presence in Dynamic Stabilization with the Dynesys® system and the Wallis® Implant, these two devices combining 38 years of clinical experience with over 75,000 surgeries performed worldwide.

Zimmer Spine EMEA Tel : +33 556 001 820 Fax : +33 556 001 821 Web: www.zimmerspine.eu

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TRADE TOOLS

Biplane Fluoroscopic Imaging Controlled clinical evidence indicated that the simultaneous biplanar fluoroscopy significantly reduced by 50% both the radiation exposure to the operating room staff and the surgery time, compared to single C-arm fluoroscopy, during minimally invasive lumbar spine surgery1.

Using simultaneous biplanar fluoroscopy, the surgeons are able to perform in safe conditions up to 420 operations per year while the C-arm fluoroscopy restricts the safe amount of surgeries up to only 210 per year.

SwemacimagingTM and their distributor partner for Europe, Pioneer Surgical TechnologyTM, now introduce the Biplanar500eTM, a unique mobile biplane digital fluoroscopy system for accurate and safer surgeries.

The Biplanar500eTM further reduces radiation due to its efficient presetting of asymmetrical collimators which use fewer images, absence of grid and its pulse mode function, eliminating the time-consuming adjustments during an operation and thus leading to reduced operating time, accurate positioning and increased sterility.

1 See article of American Academy of Orthopedic Surgeons www.aaos.org/News/aaosnow/dec08/clinical1.asp

Biplanar 500eTM

Pioneer Surgical Technology BV Tel: +31 30 693 47 20 Fax: +31 30 693 47 21 Web: www.pioneersurgical.eu Email: info@pioneersurgical.eu

BioDisc™ Spinal Disc Repair System BioDisc™ Spinal Disc Repair System, manufactured by CryoLife®, Inc. (Kennesaw, GA, USA), is a protein-based hydrogel device intended for use in post-discectomy patients for preservation of disc height, the prevention and reduction of lumbar motion segment instability, and the prevention of recurrent disc herniation. BioDisc is intended to fill the void space within the spinal disc following removal of the nucleus pulposus in the treatment of lumbar intervertebral disc herniations at the L4/L5 and L5/S1 levels. Following a discectomy, the device delivery tip is placed directly into the disc space through the annulotomy and the implant material is easily dispensed into all areas of the nuclear void. Currently, BioDisc is undergoing an investigational trial in the UK to gather basic safety and performance information in a limited number of patients over two years.

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TRADE TOOLS

M6-L: Designed to Replicate the Motion of a Natural Disc

The M6-L artificial lumbar disc is designed to replicate the anatomic structure and biomechanical performance of a natural disc. Its innovative design incorporates an artificial nucleus to allow axial compression and a woven fiber annulus for controlled range of motion in all six degrees of freedom.This physiologic motion is intended to preserve segmental motion and possibly prevent or delay additional adjacent level degeneration.

Quality of Motion assesses how well the motion of an implanted functional spine unit approximates the motion of a healthy one over the entire range of motion, not just its endpoints. Through biomechanical testing, a load vs. angular displacement curve (“kinematic signature”) is generated that allows assessment of the Quality of Motion parameters.

Biomechanical testing with the M6-L artificial lumbar disc has demonstrated equivalent Quality of Motion compared to the healthy disc.The innovative artificial fiber annulus and nucleus construct of the M6-L is the critical component in replicating this physiologic motion, as it is designed to provide the necessary restraint and control needed throughout the spine’s natural range of motion.

UK Distributor: Lindare Medical Tel: +44 (0)1233 770370 Fax: +44 (0)1233 770370 Email: customerservices@lindaremedical.co.uk Web: www.lindaremedical.co.uk

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BacJacTM Interspinous Decompression System Pioneer Surgical TechnologyTM launched P3 (Pioneer Peek-onPeek) Technology product, the BacJacTM Interspinous Decompression System.

The BacJac system is designed to relieve pain in patients with Neurogenic Intermittent Claudication (NIC) due to Lumbar Spinal Insertion Implant undeployed Stenosis (LSS).

The BacJac achieves spinal decompression by limiting the symptomatic extension while maintaining physiologic motion.

BacJac’s minimally invasive, unilateral surgical approach reduces operating room and patient recovery time, while preserving future Implant deployed surgical options.The BacJac is a self-deploying, non-fusion device which is tissue sparing and ligament preserving.

Due to its large contact area with the spinous processes and its near-physiologic modulus, the BacJac ensures a minimal risk of subsidence. Pioneer’s P3 motion preservation products offer excellent wear resistance, established biocompatibility, biodurability and radiolucency.

Pioneer Surgical Technology BV Tel: +31 30 693 47 20 Fax: +31 30 693 47 21 Web: www.pioneersurgical.eu Email: info@pioneersurgical.eu

HRC Cervical Locking Cage A remarkable innovation developed by Eurospine of Paris, the HRC Cervical Locking Cage’s unique design provides immediate stability through a simple rotation of the blade after insertion of the cage.

The design has many benefits. A patented locking mechanism with laser marked Titanium blades ensure that, once inserted, the cage is totally secure. In addition, anatomical shaping provides a perfect fit and the option of smooth finish or serrated edges offers further options. Bone graft is aided by the provision of a large surface to encourage fusion of the implant with either real or custom fit substitute bone.

Further features include an x-ray witness in the form of a titanium spot to accurately verify correct insertion. Simplified instrumentation provides ease of use and encourages swift assimilation to the surgeons skill set. Instruments also evenly distribute impact stress eliminating any risk of the cage cracking during insertion. For further information or to book a full demonstration contact Advance Health: Advance Health Tel: 0845 470 0001 E-mail: info@advancehealth.uk.com Web: www.advancehealth.uk.com

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TRADE TOOLS

The Spinos Implant

Spinos is an innovative implant for use in the treatment of low back pain. It enables the distance between the spinous processes to be maintained, while preserving full mobility.

The in-situ continuous adjustability of the interspinous distance affords dynamic stabilisation of the spinal motion segment, whilst effectively preventing narrowing of the neural foramina and excessive loading of the facet joints. At the same time all anatomical structures, including the supraspinous ligament, are preserved intact.

With the infinitely variable adjustability of distance in-situ, the functional requirements of the individual spinal motion segment can be re-established. At the same time, flexible contact areas on the spinous processes help to prevent bony atrophy and peak loading. The cone shaped, tapered point facilitates insertion of the implant into the interspinous space.

Bevelled edges allow good adaptation to the existing individual anatomy and permit simultaneous application at adjacent levels.

The implant is placed in the interspinous space using the combined holder-distractor forceps and expanded until the adequate supraspinous ligament tension is restored or the vertebral end plates are parallel, respectively. Through this gentle approach, the anatomical structures are preserved intact, kyphosis is prevented and peak loading of the spinous processes is avoided.

UK Distributor: Lindare Medical Tel: +44 (0)1233 770370 Fax: +44 (0)1233 770370 Email: customerservices@lindaremedical.co.uk Web: www.lindaremedical.co.uk

Better Vision - The Key to Higher Precision MÖLLER-WEDEL HI-R700 Haag-Streit UK is pleased to announce the release of the new HiR700 Spinal surgical microscope. The Hi-R700 is Möller-Wedel’s new multi-functional spinal microscope, individual configuration for your spinal surgery needs. “During surgery, time is an essential factor”, explains Steve Derham, Microscope Product Manager for Haag-Streit UK. “Thanks to an easy balance system and precise positioning of the Möller Hi-R700 there is less requirement for re-adjustment”.

The Hi-R700 incorporates an ingenious ‘Centre Axis’ system which allows for more natural movement and precise positioning

The M6®-C Artificial Cervical Disc The M6®-C artificial cervical disc offers an innovative option for artificial cervical disc replacement because of its unique design which is based on a natural disc’s qualities.

Engineered to replicate your own disc, the M6®-C is the only artificial disc that incorporates an artificial nucleus (made from polyurethane) and a woven fiber annulus (made from polyethylene). The M6 ®-C artificial nucleus and annulus are designed to provide the same motion characteristics of a natural disc.

Together, the M6 ®-C’s artificial nucleus and annulus provide compressive capabilities along with a controlled range of natural motion along each vertebra. This “natural” motion is designed to provide the freedom to move your neck naturally while minimising the stress to adjacent discs and other important spinal joints.

The M6®-C Cervical Disc Replacement Device is produced in Silicone Valley by Spinal Kinetics Inc, and distributed throughout the UK by Lindare Medical Ltd, the Kent based Distributor of innovative Spinal Implants and Bone grafting material. Contact the Company for further details.

Lindare Medical Tel: +44 (0)1233 770370 Fax: +44 (0)1233 770370 Email: customerservices@lindaremedical.co.uk Web: www.lindaremedical.co.uk

through effortless rotation in all three axes. The Hi-R700 has impressive optical image clarity and is highly economical due to its modular design. Furthermore, a large 25mm stereo base is also incorporated in the Hi-R700, which provides ‘realistic images’ and amazing ‘depth perception’.

Like all products from Haag-Streit UK, the Hi-R700 is supported by an after-sales service of the highest quality. Proven maintenance programmes ensure that Haag-Streit UK guarantee dependable whole-life technical support.

For further information regarding the Hi-R700, or any other Haag-Streit products, please contact Haag-Streit UK customer services.

Haag-Streit Tel: +44 (0)1279 456261

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MEETINGS

The Meetings section enables the Spinal specialist to look up congresses and training courses within the fields of Spinal Surgery, Neurology and Radiology

April 2010

19-20 April Intermediate Skills in Laparoscopic Surgery (Suturing and Anastomosis) Venue: London, UK www.rcseng.ac.uk Contact:The Royal College of Surgeons of England E-mail: generalsurgery@rcseng.ac.uk Tel: +44 (0) 20 7405 3474

London

7-8 April Bariatric Surgery Techniques (Advanced Laparoscopy) Venue: London, UK www.rcseng.ac.uk Contact:The Royal College of Surgeons of England E-mail: generalsurgery@rcseng.ac.uk Tel: +44 (0) 20 7405 3474 8-11 April 10th Annual AAOS/OTA Orthopaedic Trauma Update Venue: Rosemont, IL, USA www.aaos.org Contact: American Academy of Orthopaedic Surgeons E-mail: meeting@aaos.org Tel: +1 847 823 7186 Fax: +1 847 823 8125 9-12 April 26th International Congress of Radiology Venue: Shanghai, China Contact: ICR2010 Secretariat E-mail: ICR2010@cma.org.cn Tel: +86 10 8515 8141 12-14 April Emergency Surgery for the On-call General Surgeon Venue: London, UK www.rcseng.ac.uk Contact:The Royal College of Surgeons of England E-mail: generalsurgery@rcseng.ac.uk Tel: +44 (0) 20 7405 3474

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19-21 April Core Skills in Laparoscopic Surgery Venue: London, UK www.rcseng.ac.uk Contact:The Royal College of Surgeons of England E-mail: generalsurgery@rcseng.ac.uk Tel: +44 (0) 20 7405 3474 San Francisco

Venue: Liverpool, UK www.britspine.org Contact: Sue Woodward E-mail: sue.britspine@ntlworld.com

May 2010 1-6 May 78th AANS Annual Meeting Venue: Philadelphia, PA, USA www.aans.org Contact: American Association of Neurological Surgeons E-mail: info@aans.org Tel: +1 847 378 0500 Fax: +1 847 378 0600 7 May Legal Aspects of Surgical Practice Venue: London, UK www.rcseng.ac.uk Contact:The Royal College of Surgeons of England E-mail: generalsurgery@rcseng.ac.uk Tel: +44 (0) 20 7405 3474

June 2010

22-24 April 5th Annual San Francisco Orthopaedic Trauma Symposium Venue: San Francisco, CA, USA www.ocme.ucsf.edu Contact: UCSF Office of Continuing Medical Education E-mail: info@ocme.ucsf.edu Tel: +1 415 476 4251 27-29 April Operative Skills in Neurosurgery Venue: London, UK www.rcseng.ac.uk Contact:The Royal College of Surgeons of England E-mail: generalsurgery@rcseng.ac.uk Tel: +44 (0) 20 7405 3474 28-30 April Britspine 2010

2-5 June 11th EFORT Congress Venue: Madrid, Spain www.efort.org Contact: RĂŠgine BrĂźhweiler E-mail: regine.bruehweiler@efort.org Tel: +41 444 484 405 Fax: +41 444 484 411 8-9 June Clinical Skills in Spinal Assessment and Management Venue: London, UK www.rcseng.ac.uk Contact:The Royal College of Surgeons of England E-mail: generalsurgery@rcseng.ac.uk Tel: +44 (0) 20 7405 3474 9-10 June 14th ESSKA Congress Venue: Oslo, Norway Contact: Congress Secretariat E-mail: esska@intercongress.de Tel: +49 0611 77160

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MEETINGS

10-11 June Society for Back Pain Research Venue: Odense, Denmark www.sdu.dk Las Vegas

20-25 June 3rd International Conference on Osteoimmunology: Interactions of the Immune and Skeletal Systems Venue: Santorini, Greece Contact: Conference Secretariat E-mail: 3rdOsteoimmunology@aegeanconferences.org Tel: +1 610 527 7630 23-26 June CARS 2010 - Computer Assisted Radiology and Surgery - 24th International Congress and Exhibition Venue: Geneva, Switzerland www.cars-int.org Contact: CARS Conference Office - Mrs. Franziska Schweikert E-mail: office@cars-int.org Tel: +49 7742 922 434 Fax: +49 7742 922 438 30 June - 2 July Technical Advances to Skull Base Surgery Venue: London, UK www.rcseng.ac.uk Contact:The Royal College of Surgeons of England E-mail: generalsurgery@rcseng.ac.uk Tel: +44 (0) 20 7405 3474

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18-21 July 1st Society of Curacao Orthopedic Surgeons, Radiologists and Trauma Surgeons (SOCORT) Bi-Annual Meeting Venue: Curaรงao, Netherlands Contact: J.L. Bloem E-mail: j.l.bloem@lumc.nl 21-24 July The 17th Scoliosis Research Society (SRS) International Meeting on Advanced Spine Techniques Venue:Toronto, Canada www.srs.org Contact: Meetings Department E-mail: meetings@srs.org Tel: +1 414 289 9107 Fax: +1 414 276 3349

14-17 June National Neurotrauma Symposium Venue: Las Vegas, NV, USA www.neurotrauma.org Contact: Karen Gottlieb E-mail: NNS@neurotrauma.org Tel: +1 305 661 5581 Fax: +1 305 661 0709

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26-30 July 7th Annual Meeting of the Society of Neurointerventional Surgery (SNIS) Venue: Carlsbad, CA, USA www.snisonline.org Contact: Meeting Organiser E-mail: info@snisonline.org Tel: +1 703 691 2272

21-24 September Scoliosis Research Society 45th Annual Meeting & Combined Course Venue: Kyoto, Japan www.srs.org Contact: Scoliosis Research Society Meetings Department E-mail: meetings@srs.org Tel: +1 414 289 9107 Fax: +1 414 276 3349 24-25 September 8th Interventional MRI Symposium Venue: Leipzig, Germany Contact: Department of Diagnostic and Interventional Radiol Tel: +493 419 717 400

October 2010 3-7 October American College of Surgeons 96th Annual Meeting Venue:Washington, DC, USA www.facs.org Contact: American College of Surgeons E-mail: postmaster@facs.org Tel: +1 312 202 5000 Fax: +1 312 202 5001 Washington DC

August 2010 31 August - 3 September 7th SICOT/SIROT Annual International Conference Venue: Gotheburg, Sweden www.sicot.org Contact: Conference Secretariat E-mail: congress@sicot.org Tel: +32 2648 6823 Fax: +32 2649 8601

September 2010 1-4 September BIOSPINE 3 - 3rd International Congress Biotechnologies for Spinal Surgery Venue: Amsterdam,The Netherlands www.biospine.org Contact: Congrex Deutschland GmbH E-mail: biospine@congrex.com Tel: +49 (0)30 25 89 46 2 Fax: +49 (0) 30 25 89 41

5-9 October 25th Annual Meeting of the North American Spine Society (NASS) Venue: Orlando, FL, USA Contact: North American Spine Society E-mail: info@spine.org Tel: +1 (877) 774-6337 12 October Neuro-Oncology Venue: London, UK www.rcseng.ac.uk Contact:The Royal College of Surgeons of England E-mail: generalsurgery@rcseng.ac.uk Tel: +44 (0) 20 7405 3474

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MEETINGS

19-20 October Specialty Skills in Emergency Surgery and Trauma Venue: London, UK www.rcseng.ac.uk Contact:The Royal College of Surgeons of England E-mail: generalsurgery@rcseng.ac.uk Tel: +44 (0) 20 7405 3474 31 October - 4 November 38th Annual Meeting of the International Society for Pediatric Neurosurgery Venue: Jeju, Republic of Korea Contact: Conference Secretariat E-mail: ispn@broad-water.com Tel: +630 681 1040

November 2010 4-6 November 5th International Symposium on

Microneurosurgical Anatomy (5th ISMA) Venue: Istanbul,Turkey www.isma2010.org Contact: Secretariat E-mail: isma@isma2010.org Tel: +90 312 440 5600 Fax: +90 312 440 5597 9-12 November 7th Interdisciplinary World Congress on Low Back & Pelvic Pain Venue: Los Angeles, CA, USA www.ucsd.edu Contact: UCSD CME E-mail: ocme@ucsd.edu

Tel: +1 858 534 3940 Fax: +1 858 822 5908 13-18 November 10th Asian-Oceania International Congress on Skull Base Surgery (AOSBS) in conjunction with WFNS Skull Base Course, Asian Australasian Society of Neurological Surgeons (AASNS) Course and World Academy Venue: Bali, Indonesia Contact: Santi Anwar E-mail: aosbs2010@pharma-pro.com Tel: +62 21 5596 0180 Fax: +62 21 5596 0179

If you would like your event listed free of charge in Meetings, please forward details to: The Editor, Spinal Surgery News, 2 Cheltenham Mount, Harrogate HG1 1DL Tel: +44 1423 569676 Fax: +44 1423 569677 E-Mail: editor@spinalsurgerynews.com If you would like to reproduce our list, please place an acknowledgement to SSN in your text.

Subscribe today £24 for UK residents £32 for Europe £42 for Overseas Call: +44 (0)1423 569676 Email: gaye@spinalsurgerynews.com Web: www.spinalsurgerynews.com

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ARTICLE

Pyogenic Spondylodiscitis

Ranjit Pande, FRCS (Tr & Orth ) Senior Fellow, Cardiff Spine Unit Sashin Ahuja, FRCS (Tr & Orth ) Consultant Spine Surgeon, Cardiff Spine Unit

Introduction Evidence of spinal infection exists in Egyptian mummies (c.3000 BC) and Neolithic remains from earlier. The earliest scientific descriptions came from Hippocrates, but it was enunciated in more detail by Percival Pott (1779), Nelaton (1854) and Rodet (1884)1. Mortality before antibiotics was upto 70%. Even today, diagnostic delay is three months on average and recovery averages 12 months or more. Its incidence may be increasing due to greater numbers of immunocompromised patients and an increase in spinal invasive procedures.

Definitions Involvement of the disc alone is commonly referred to as discitis. Infection of the vertebral body is termed vertebral osteomyelitis.

Spondylodiscitis best describes the condition where the infection involves both, the vertebral body and the disc, after having crossed the end-plate from the former to the latter. Each of these may be associated with epidural or paravertebral abscesses.

Biologic Anatomy Spinal infection may be acquired by hematogenous spread through bacteremia from distant sites or by direct spread secondary to trauma, surgery or adjacent infections. Urologic procedures and indwelling catheters are frequently responsible for bacteremia and seeding in spinal tissue.

Arterially spread infection originates in the end plate and involves the disc secondarily. The microscopic and macroscopic anatomy of the disc plate and its relation to the contiguous end plates has been well described by Coventry 2, Inou 3, Wiley & Trueta 4 & Whalen 5. Batson 6 expanded Breschet’s description of pelvic venous drainage and its relation to the spine while Crock

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& Yoshizawa described the microvascular circulation of the end plate 7.

Ratcliffe8, described changes in the end plate vasculature with age. Intraosseous arteries tend to be end arteries in adults, causing greater involvement of bone due to a septic embolus, thus leading to a greater incidence of vertebral osteomyelitis. The Nucleus Pulposus has a much greater blood flow through the adjacent end plates and the annulus in children, thus resulting more in discitis.

Natural History Blood borne infection probably begins in the capillary loops or post capillary venous channels in the end plate. Sludging here leads to suppurative inflammation, tissue necrosis, bony collapse and spread into adjacent disc spaces.

Anterior or posterior extension can cause paravertebral or epidural abscesses.

Infected bone softens and may collapse.

Neurologic deficit may occur due to epidural abscess or neural compression due to pathological fracture.

Eismont9 described an increased incidence of paralysis with increasing age, higher level of involvement, co existing debility (diabetes, rheumatoid arthritis, steroid use etc.) and staphylococcus aureus infection.

Causative Organisms A variety of organisms are implicated in pyogenic spondylodiscitis. Staphyococcus aureus is by far the most common, being isolated in 50 – 60% cases. Table 1 summarises the rest11.

In addition to Table 1, there are case reports describing spondylodiscitis due to Gardnerella vaginalis 12, Eikenella corrodens 13, Propionibacterium acnes 14, Scedosporium prolificans15, Hemophilus aphrophilus 16 and Blastoschizomyces capitatus17.

Well known associations exist between Pseudomonas and IV drug abuse, Gramnegative organisms such as Escherechia, Klebsiella and proteus with genitourinary disease, Salmonella and Sickle cell disorders. Infections secondary to Spinal instrumentation can involve staphylococcus epidermidis.

Clinical Features and Diagnosis Ross and Fleming18 reported pain as the primary symptom in 85% patients with Spondylodiscitis. Constitutional symptoms such as fever, night sweats, weight loss etc may be present. Puig–Guri 19 described four possible clinical syndromes in Spine infections: Hip Joint syndrome, Abdominal syndrome, Meningeal

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ARTICLE

Figure 1: Indications for surgery in spondylodiscitis:

Causative Organisms in Pyogenic spondylodiscitis: Staphylococcus aureus Strptococcus species Staphylococcus epidermidis Escherechia coli Klebsiella pneumoniae Proteus species Pseudomonas aeruginosa Enterobacter species Salmonella species Serratia marcescens Brucella species Acinetobacter species

Figure 1: Radiological changes in Spondylodiscitis: Sclerosis, Vertebral body destruction and reduction in disc height

Figure 2a: Spondylodiscitis changes on T1 weighted images in MRI

Figure 2b: Spondylodiscitis changes on T2 weighted images in MRI

Figure 3: Posterior fusion in Spondylodiscitis

syndrome and Back Pain syndrome.

Neurological deficit can be early if due to epidural abscess or late if secondary to

deformity. Neurology due to arterial thrombosis is rare20. Infants may show irritability; toddlers may exhibit difficulty

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walking or eventually, refusal to walk.

Muscle spasm can be pronounced. Postoperative spondylodiscitis may present with a discharging wound, commonly one – two weeks post surgery.

Xue & Guan21 found an elevated CRP and ESR in all 23 patients in their series.

White cell counts were less reliable. Very elevated white cell counts may however suggest epidural abscess development.

Low platelet counts (< 100 x 10(9)/L), extremely high ESR (> or = 110 mm/h) and cervical spine epidural abscess may be predictors of a poor outcome22.

X-Ray findings of Spondylodiscitis include disc space narrowing, end plate irregularity, subchondral defects and sclerosis. These may appear two weeks to three months after onset of infection 23. Paravertebral masses indicate abscess formation. Vertebral collapse, segmental kyphosis and bony ankylosis are late findings.

CT scans offer a qualitative improvement over plain X rays. They also have an application in guided biopsies and paravertebral abscess aspiration.

MRI scanning is the diagnostic modality of choice. Modic reported MRI sensitivity of 96%, specificity 92% and accuracy of 94% in disc space infections24. Ring enhancement of epidural abscesses on Gadolinium scanning may be an indication for surgery25. MRI is contraindicated in the presence of metallic heart valves or pace makers. Presence of metallic joint prostheses or claustrophobia are relative contraindications for MRI scanning.

Where MRI scanning is not feasible, Radionuclide scanning may be of use.

Combined Tc99 and Ga 67 scanning is reported to be 90% sensitive, 100% specific and 94% accurate for infection. Indium 111 labelled leucocyte scanning is highly specific but not sensitive enough.

A Diagnostic biopsy is most often undertaken under CT guidance to isolate the offending pathogen and rationalise choice of antibiotics. A recent level 3 study has reported identification of causative bacteria in 47% CT guided biopsies as against 90% endoscopic biopsies 26. Other studies have however reported success rates for percutaneous needle biopsies ranging from 71% to 90% 27.

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Figure 2: Indications for surgery in spondylodiscitis:

Indications for surgery in spondylodiscitis: Failure of non operative treatment Neurologic compromise ( static or progressive ) Sepsis Spinal instability Progressive or advanced spinal deformity Refractory pain Need for pathogen identification

Differential Diagnosis Spondylodiscitis should be differentiated from primary or metastatic malignancies of the spine, metabolic bone diseases with

pathologic fractures and infections in the vicinity including the psoas, abdominal cavity and hip. Charcots arthropathy of the spine should be kept in mind.

Treatment Non operative management with antibiotics and bracing continues to be first line management in adult spondylodiscitis.

Elimination of spinal pain and spontaneous fusion are the expected end points.

Bettini and Girardo28 have recently reported on their series of 56 adult patients with spondylodiscitis. They were able to treat all their patients with iv antibiotics for an average of 8.5 weeks followed by oral antibiotics and supportive spinal bracing.

They monitored CRP response, ESR and WCC count as a guide for duration of antibiotic therapy.

Indications for surgery in spondylodiscitis are enumerated in Table 2 (11): In addition to Table 2, advanced age (>

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60 yrs) and immunocompromise are regarded as bad prognostic factors and are relative indications for surgery.

The principles of surgical treatment are adequate debridement, decompression of neurological structures and rigid fixation.

Surgical options include anterior or posterior approaches, with decompression, debridement and fusion. Although autogenous structural bone graft has been used traditionally, there are studies reporting the use of titanium29 and PEEK30 cages being used successfully. Posterior fusion as a second stage after an anterior procedure is indicated when treating a severe kyphot-

ic deformity or where multilevel corpectomy has been performed.

Lee and Suh31 have reported on their series of 18 patients with spondylodiscitis treated with posterior lumbar interbody fusion. All patients fused well, though one took 18 months to do so.

Linhard and Kruger32 in a randomised trial comparing isolated anterior and posterior fusion for spondylodiscitis found no statistical differences in fusion rates and results at one year. The anterior fusion group mobilised earlier while the posterior group had lesser blood loss intra-op.

Results of posterior decompression without fusion in spondylodiscitis have historically been poor.

Summary Pyogenic Spondylodiscitis most often presents with back pain and muscle spasm. Primary hematogenous infection is more common than external seeding.

MRI scans are the best imaging modality, while serial CRP helps monitor response to treatment. Antibiotics are the mainstay of non-operative management. Surgery in the form of decompression and fusion may be required.

References 1

Campbells Operative Orthopaedics, Ed 8, Mosby, 3791

2

Coventry MB, Ghormley RK, Kernohan JW: The intervertebral disc: its

a retrospective analysis of 37 cases. Clin Orthop 118:1890, 1976 19

microscopic anatomy and pathology. JBJS 27-A: 105, 1945 3

Inou H: Three dimensional architecture of lumbar intervertebral discs,

clinical and roentgenographic observations. JBJS 28: 29,1946 20

Spine 6:139, 1981 4

69:110,1988 21

23 patients. Zhonghua Wai Ke Za Zhi, 15:47(2):109-11 22

discs, J Paediatr Orthop 5:403, 1985

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spondylodiscitis of the lumbar spine; evaluation of a new MRI staging

Eismont FJ, Bohlman HH, Soni PL et al: Pyogenic and fungal osteomyelitis with

classification and imaging findings as indicators of surgical management: a retrospective study of 37 patients. Acta Orthop Trauma Surg (Epub) 2009

Wood GW II, State of the art and review, spine: spinal infection, vol 3, no 3,

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Philadelphia, 1989, Hanley & Belfus, Inc 11

Eastlack RK, Kauffman CP, Spine, Ed Bono CM, LW&W, 2004

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Graham S, Howes C, Dunsmuir R, Sandoe J: Vertebral osteomyelitis and discitis

Tsai J, Huang TJ, Huang CC, Li YY, Hsu RW: Eikenella corrodens discitis in a

Clin Orthop 466, No 12, 3086-92,2008 27

Uckay I, Dinh A, Vauthey L: Spondylodiscitis due to Propionibacterium acnes:

Vol 79,660 – 664,2008

Garcia-Vidal C, Cabellos C, Ayats J: Fungal postoperative spondylodiscitis due to

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Scedosporium proloficans. Spine J.9(9):e1-7 Epub 2009 Chien JT, Lin CH, Chen YC: Epidural abscess caused by Hemophilus aphrophilus

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Lee JS, Suh KT: Posterior lumbar interbody fusion with an autogenous iliac crest bone graft in the treatment of pyogenic spondylodiscitis, JBJS Vol 88(B), Issue 6, 765 – 770,2006

Celik AD, Ozaras R, Kantarcioglu S: Spondylodiscitis due to an emergent fungal pathogen: Blastoschizomyces capitatus, a case report and review of literature.

Mondorf Y, Gaab MR, Oertel JM: PEEK cage cervical ventral fusion in spondylodiscitis, Acta Neurochir (Wien), Epub 2009

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misdiagnosed as pasteurella species. Intern Med 48(10):853-8,Epub 2009 17

Robinson Y, Tschoeke S, Finke T: Successful treatment of spondylodiscitis using titanium cages: a 3 year follow up of 22 consecutive patients, Acta Orthopaedica

(Epub ahead of print)

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Bettini N, Girardo M, Dema E, Cervellati S: Evaluation of conservative treatment of non specific spondylodiscitis, Eur Spine J 18 Suppl 1: 143-50, 2009

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report of 29 cases and a review of literature, Clin Microbiol Infect, Jun6 2009

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Stoker DJ, Kissin CM: Percutaneous vertebral biopsy: a review of 135 cases, Clin Radiol 36:569, 1985

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habitual betel quid chewer: a case report, Spine 34(9):E333-6,2009 14

Yang SC, Fu TS, Chen LH: Identifying pathogens of spondylodiscitis; percutaneous endoscopy or CT guided biopsy.

due to Gardnerella vaginalis, J Med Microbiol 58 (Pt 10):1382-4, 2009 13

Uchida K, Nakajima H, Yavama T: Epidural abscess associated with pyogenic

J Anat 134 (Pt 2 ): 373 – 82, 1982

paralysis, JBJS 65-A:19-29,1983 10

Modic T, Masaryk T, Plaushtek D: Magnetic resonance imaging of the spine, Radiol Clin North Am 14:229, 1986

Ratcliffe JF: An evaluation of the intra-osseous arterial anastomoses in the human vertebral body at different ages. A microarteriographic study,

Waldvogel FA, Vasey H: Osteomyelitis: The past decade: N Engl J Med 303:360,1980

Crock HV, Yoshizawa H: The blood supply of the lumbar vertebral column, Clin Orthop 115: 6, 1976

Tang HJ, Lin HJ, Liu YC, Li CM: Spinal epidural abscess – experience with 46 patients and evaluation of prognostic factors, J Infect 45(2):76-81,2002

Batson OV: The function of the vertebral veins and their role in the spread of metastases, Ann Surg 112: 138, 1940

Xue W, Guan XL, Liu L: Adult hematogenous pyogenic discitis and vertebral osteomyelitis: clinical features, diagnostic, therapeutic approaches and outcome in

Whalen JL, Parke WW, Mazur JM, Staufer ES: The intrinsic vasculature of developing vertebral endplates and its nutritive significance to the intervertebral

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Feldenzer JA, McKeever PE, Schaberg DR: The pathogenesis of spinal epidural space abscess: microangiographic studies in an experimental model, J Neurosurg

Wiley AM, Trueta J: The vascular anatomy of the spine and its relationship to pyogenic vertebral osteomyelitis, JBJS 41-B:796,1959

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Puig – Guri J: Pyogenic osteomyelitis of the spine: differential diagnosis through

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Linhardt O, Krüger A, Krödel A: First results of anterior versus posterior

Rheumatol Int 29(10):1237-41.Epub 2009

instrumentation-fusion in the treatment of spondylodiscitis, Z Orthop Ihre

Ross PM, Fleming JL: Vertebral body osteomyelitis: spectrum and natural history:

Grenzgeb;142(1):73-8,2004

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Expression of cartilage-derived morphogenetic protein in human intervertebral discs and its effect on matrix synthesis in degenerate human nucleus pulposus cells Christine L Le Maitre1,2, Anthony J Freemont2 and Judith A Hoyland2 1

Biomedical Research Centre, Biosciences, Faculty of Health and Wellbeing, Sheffield Hallam University, City Campus, Owen Building, Howard Street, Sheffield, S1 1WB, UK 2 Tissue Injury and Repair Group, School of Clinical and Laboratory Sciences, Faculty of Medical and Human Sciences, Stopford Building, The University of Manchester, Oxford Road, Manchester, M13 9PT, UK Arthritis Research & Therapy 2009, 11:R137doi:10.1186/ar2808 © 2009 Le Maitre et al.; licensee BioMed Central Ltd.

Abstract Introduction Loss of intervertebral disc (IVD) matrix and ultimately disc height as a result of ‘degeneration’ has been implicated as a major cause of low back pain (LBP). The use of anabolic growth factors as therapies to regenerate IVD matrix, hence restoring disc height and thus reversing degenerative disc disease, has been suggested. Cartilage-derived morphogenetic protein (CDMP) is a growth factor which stimulates proteoglycan production in chondrocyte-like cells and thus could be a useful growth factor for LBP therapies. However, little is known about the expression of CDMP or its receptor in human IVD, nor its effects on human disc cells.

Methods Using immunohistochemistry we investigated the localisation of CDMP in non-degenerate and degenerate human IVDs. Additionally, we investigated the effect of CDMP on aggrecan and type II collagen gene expression and proteoglycan synthesis in nucleus pulposus (NP) cells derived from degenerate IVDs. Results We demonstrated that CDMP 1 and 2 were expressed in the non-degenerate and degenerate IVD, particularly in cells of the NP. A small decrease in the number of CDMP 1 and 2 immunopositive cells was seen with degeneration. Treatment of human NP cells, (derived from degenerate IVD), with CDMP showed an increase in aggrecan and type II collagen gene expression and increased production of proteoglycan (GAGs).

Conclusions The data suggests that CDMP may be a useful growth factor to stimulate proteoglycan production in the human degenerate IVD and hence the repair of the extracellular matrix.

Background Low back pain (LBP) is a major problem in the western world, affecting approximately 11 million people in the UK for at least one week each month1. It leads to a considerable loss of working days and has a significant impact on the national health service2. Imaging studies indicate

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a link between degeneration of the intervertebral disc (IVD) and LBP 3,4.

However, current conservative and invasive interventions for IVD degeneration, aimed at improving LBP, are only directed towards symptomatic relief.

Currently, there are few treatments aimed at repairing the degenerate IVD,

which if developed could not only relieve symptoms but prevent their reoccurrence through restoration of normal IVD structure and function. Modern advances in therapeutics, particularly cell and tissue engineering, offer potential methods for inhibiting or reversing IVD degeneration that have not previously been possible.

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However, to ensure success they require a greater level of understanding of the pathobiology of IVD degeneration than is currently available5.

The IVD is composed of a proteoglycan rich nucleus pulposus (NP), which is constrained by the surrounding annulus fibrosus (AF) and cartilaginous endplates.

During IVD degeneration there is a change in cell phenotype resulting in decreased matrix production, particularly proteoglycan synthesis, and an increase in degradation of IVD matrix by locally produced matrix metalloproteinases (MMPs) and ADAMTS (a disintegrin and metalloprotease with thrombospondin motifs)6,7.

The overall loss of normal disc matrix results in decreased weight bearing capacity, leading to the generation of fissures, annular tears and the generation of pain.

Several studies have suggested the use of anabolic growth factors to regenerate the matrix of the IVD and hence restore disc height, thereby reversing degenerative disc disease. Numerous growth factors have been implicated and those that have attracted the most attention include transforming growth factor (TGF), insulin-like growth factor (IGF), bone morphogenetic proteins (BMPs), cartilage derived morphogenetic proteins (CDMPs) and fibroblast growth factor (FGF). All these factors have been investigated in in vitro studies together with some in vivo animal studies, and due to their ability to stimulate the synthesis of matrix components of the IVD, (particularly proteoglycans), have been postulated to be therapeutic agents for the restoration of IVD matrix8-15. Our previous study investigating the localisation of these growth factor receptors, demonstrated expression of TGF RII, FGF R3 and IGF RI in the endothelial cells of blood vessels, as well as the native IVD cells. This suggests that the addition of such growth factors may induce blood vessel ingrowth, which could be detrimental in any treatment, because it has been reported that this is also accompanied by nerve ingrowth 16. In contrast BMP RII expression was not observed in blood vessels suggesting that growth factors which utilise these receptors (i.e.

BMPs and CDMPs) may be preferable agents for the regeneration of disc matrix in disc degeneration17.

Two growth factors thought to stimulate proteoglycan synthesis in chondrocyte-like cells are CDMP 1 and CDMP 2 also known as BMP 14 and BMP 13 or growth and differentiation factor (GDF) 5 and 6, respectively. The distribution and effects of these growth factors have been studied in human articular cartilage in vitro18,19. In addition, the effect of these growth factors in animal models of IVD degeneration has also been studied but their expression in or effect on human IVD cells is still not fully understood9,20-22.

Here we investigated the expression and localisation of CDMP 1 and 2 in non-degenerate and degenerate human IVDs to ascertain how their expression alters with IVD degeneration. We have previously investigated the expression of the CDMP receptor and here we relate the expression and distribution of CDMP to that seen previously for the receptor BMP RII17. Furthermore, the effect of CDMP 1 on cell proliferation, aggrecan and collagen type II gene expression and proteoglycan production in human NP cells derived from degenerate discs was also investigated.

Materials and methods Tissue samples Human IVD tissue was obtained either during surgery or post mortem examination with informed consent of the patient or relatives. Local research ethics committee approval was given for this work by the following Local Research Ethics Committees: Salford and Trafford, Bury and Rochdale, Central Manchester and Her Majesty’s coroner.

Post mortem tissue Discs recovered from patients within 18 hours of death consisted of full thickness wedges of IVD of 120° arc removed anteriorly. This allowed well-orientated blocks of tissue incorporating AF and NP to be cut for histological study. Patients with a history of sciatica sufficient to warrant seeking medical opinion, were excluded from the study.

Surgical tissue Patients were selected on the basis of IVD degeneration diagnosed by magnetic resonance imaging and progression to anterior resection either for spinal fusion or disc

replacement surgery for chronic LBP. Patients experiencing classical sciatica were excluded from the study. Some patients underwent fusion at more than one disc level because of spinal instability. Occasionally the specimens retrieved from multilevel fusion included discs with low (0 to 3 [see below for details of the scoring system]) histological scores (i.e. morphologically normal) at one level (Table 1). Wedges of disc tissue were removed in a manner similar to that described for cadavers.

General procedure for tissue specimens A block of tissue, incorporating AF and NP in continuity was fixed in 10% neutral buffered formalin, decalcified in EDTA and processed into paraffin wax. Sections were taken for H&E staining to score the degree of morphological degeneration according to previously published criteria23. A score of 0 to 3 represents a histologically normal (non-degenerate) disc, 4 to 8 indicates evidence of intermediate degeneration and 9 to 12 indicated severe degeneration. From this histological scoring, 30 discs were selected to represent a range of scores from non-degenerate (grades 1 to 3) up to the most severe level of histological degeneration (grade 12).

Localisation of CDMP 1 and 2 Immunohistochemistry (IHC) was used to localise the growth factors CDMP 1 and 2 within the 30 disc samples (Table 1). The IHC protocol followed was as previously published6. Briefly, 4 µm paraffin sections were dewaxed, rehydrated and endogenous peroxidase blocked using hydrogen peroxide. After washing in distilled water sections were treated with chymotrypsin enzyme antigen retrieval system (0.01% w/v chymotrypsin (Sigma, Gillingham, Dorset, UK) for 20 minutes at 37°C). Following washing, non-specific binding sites were blocked at room temperature for 45 minutes in 25% w/v donkey serum in 1% w/v BSA (Sigma, Gillingham, Dorset, UK). Sections were incubated overnight at 4°C with goat polyclonal primary antibodies against human CDMP 1 (1:200 dilution, SantaCruz biotechnology, SantaCruz, California, USA) and CDMP 2 (1:500 dilution, SantaCruz biotechnology, SantaCruz, California, USA). Negative

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Table 1. Patient details and grades of tissues used for immunohistochemistry analysis

erate discs (scores 0 to 3). These tests were performed for each area of the disc analysed (i.e. NP, IAF and OAF). In addition Wilcoxon paired samples tests were used to compare proportions of immunopositive cells in the different areas of the discs (i.e. NP v/s IAF, NP v/s OAF and IAF v/s OAF). This analysis was performed using all disc sections regardless of level of degeneration.

Effect of CDMP on human NP samples in alginate culture Isolation of disc cells Samples of degenerate IVD tissue were obtained from three patients undergoing surgery for disc replacement for the treatment of chronic LBP (75-year-old male (Grade 7); 37-year-old female (Grade 9); and 35-year-old female (Grade 10)). NP tissue was separated and finely minced and digested with 2 U/ml protease (Sigma, Gillingham, Dorset, UK) in DMEM + F12 media for 30 minutes at 37°C and washed twice in DMEM + F12.

NP cells were isolated in 0.4 mg/ml collagenase type 1 (Gibco, Paisley, UK) for four hours at 37°C.

controls in which goat immunoglobulin (Ig) Gs (Dako, Ely, Cambridgeshire, UK) replaced the primary antibody (at an equal protein concentration) were used.

After washing, sections were incubated in a 1:300 dilution of biotinylated donkey anti-goat antiserum (SantaCruz biotechnology, SantaCruz, California, USA) for 30 minutes at room temperature.

Disclosure of secondary antibody binding was by the streptavidin-biotin complex (Dako, Ely, Cambridgeshire, UK) technique with 3,3’-diaminobenzidine tetrahydrochloride solution (Sigma, Gillingham, Dorset, UK). Sections were counterstained with Mayers Haematoxylin (Raymond A Lamb, Eastbourne, East Sussex, UK), dehydrated and mounted in XAM (BDH, Poole, UK).

Image analysis All slides were visualised using Leica RMDB research microscope and images

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captured using a digital camera and Bioquant Nova image analysis system (BIOQUANT Image Analysis Corporation, Nashville TN, USA). Each section was divided into three areas for analysis: the NP, inner annulus fibrosus (IAF) and outer annulus fibrosus (OAF) and analysed separately. Within each area 200 cells were counted and the number of immunopositive cells expressed as a proportion of this. Averages and standard deviations were calculated for disc sections grouped with the scores 0 to 3, 4 to 8 and 9 to 12. Data was then presented as means ± standard errors.

Statistical analysis Data was non-parametric and thus Kruskal Wallis with all pair-wise comparisons post hoc test Conover-Inman was used to compare the numbers of immunopositive cells in degenerate groups (4 to 8, and 9 to 12) to non-degen-

Alginate culture It is well recognised that cells derived from IVDs change their morphology and phenotype in monolayer culture becoming similar to fibroblasts. However, culturing the cells in systems such as alginate can restore the IVD cell phenotype24.

We therefore used cells in alginate beads to investigate the effects of CDMP on cell proliferation, gene expression for aggrecan and type II collagen and proteoglycan production.

Following isolation, cells were expanded in monolayer culture for two weeks prior to trypsinisation and resuspension in 1.2% w/v medium-viscosity sodium alginate (Sigma, Gillingham, Dorset, UK) in 0.15 M NaCl at a density of 4 x 106 cells/ml and alginate beads polymerised via extrusion through a 19-gauge needle into 200 mM CaCl2. Following washes in 0.15 M NaCl beads were transferred to culture plates and 2 ml of complete culture medium was then added to each well and cultures maintained at 37°C in a humidified atmosphere containing 5% CO2.

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Treatment of cells with CDMP Following one week in this culture system, cells were treated for two weeks with either 0 ng/ml or 10 ng/ml CDMP 1 (Autogen Bioclear, Wiltshire, UK); all treatments were performed six times.

Media was changed and CDMP replaced every 48 hours. Conditioned media at each media change was frozen at -20°C for further analysis.

Papain digest and DMMB assay Following treatments, triplicate samples (six beads per sample) were used for quantification of DNA and glycosaminoglycans (GAG) content using the pico green assay (Invitrogen, Paisley, UK) and the dimethylmethylene blue (DMMB) assay.

The beads were solubilised by incubation for 20 minutes at 4°C in dissolving buffer containing 55 mM sodium citrate, 30 mM Na2EDTA and 0.15 M NaCl, pH 6.8. The resulting suspension was subjected to mild centrifugation (100 g for 10 minutes) to separate the cells and their associated matrix in the pellet (cell-associated matrix (CM) compartment) from molecules derived from the matrix further removed from the cell surface in the supernatant (further removed matrix (FRM) compartment) as described previously25. The fractions were separated into fresh tubes and digested overnight at 60°C in 500 µl 20 mM sodium phosphate buffer (pH 6.8) containing 1 mM EDTA, 2 mM dithiothereitol and 100 units of papain (Sigma, Gillingham, Dorset, UK).

DMMB assay was then performed using

25 µl of shark chondrotin sulphate (Sigma, Gillingham, Dorset, UK) standards (62.5 µg/ml, 31.25 µg/ml, 15.625 µg/ml, 7.81 µg/ml, 3.9 µg/ml and 0 µg/ml), 5 µl papain digested CM samples or 5 µl papain digested FRM samples or 50 µl conditioned media collected at each media change.

Each sample was applied in duplicate in separate wells of a 96-well plate and 200 µl of DMMB colour regent (as described previously26) was added to each well. Following mixing, absorbance at A525 nm was read immediately using a Titertex Multiscan® MC (Thermo Fisher, Paisley, UK). The concentration of GAGs present within each sample and total GAGs accumulated in the media over the two weeks was calculated. DNA from papain digests of cell-associated fractions were assayed along with calf thymus DNA standards using the Pico Green DNA quantification kit as per manufactures’ instructions. GAG concentration was then normalised to DNA content per bead and means and standard errors calculated. In addition DNA content per bead was calculated as an indication of cell proliferation.

RNA extraction, and reverse transcription Following treatments, triplicate alginate bead samples (six beads per sample) were used for analysis of aggrecan and type II collagen gene expression. RNA was extracted using TRIzol® l reagent (Gibco, Paisley, UK). Prior to TRIzol® extraction, alginate constructs were washed in 0.15 M NaCl and dissolved in dissolving buffer

(55 mM sodium citrate, 30 mM EDTA, 0.15 M NaCl; pH 6) at 37°C for 15 minutes and then digested in 0.06% w/v collagenase type I (Gibco, Paisley, UK) for 30 minutes to allow digestion of matrix.

Following RNA extraction, reverse transcription was performed using avian myeloblastosis virus reverse transcriptase (Roche, East Sussex, UK).

Real-time PCR Real-time PCR was used to investigate the effects of CDMP on aggrecan (FP: 3’CCG TGT GTC CAA GGA GAA GG 5’; probe: 3’FAM- CTG ATA GGC ACT GTT GAC - MGB 5’; RP: 3’ GGG TAG TTG GGC AGT GAG AC 5’) (Accession numbers: [GenBank:NM_001135.2] (variant 1) and [GenBank:NM_013227.2] (variant 2) primers recognise both variants; Applied Biosystems, Warrington, UK) and type II alpha 1 collagen (FP: 3’ ATG GAG ACT GGC GAG ACT TG 5’; probe: 3’ FAM - CCC AAT CCA GCA AAC G - MGB 5’; RP: GCT GCT CCA CCA GTT CTT 5’) (Accession numbers: [GenBank:NM_001844.4] (variant 1) and [GenBank:NM_033150.2] (variant 2) primers recognise both variants; Applied Biosystems, Warrington, UK) gene expression using 18 s as the housekeeping gene (PDAR: Applied Biosystems, Warrington, UK) and genomic DNA standard curves to generate copy number per 100 ng cDNA as described previously27.

Statistical analysis Mann Whitney U tests were used to compare untreated and CDMP-treated sam-

Table 2. Analysis of immunohistochemical data: P values for analysis of CDMP1 and 2 expression in different areas of disc in nondegenerate v/s degenerate discs

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Figure 1. Examples of immunohistochemical staining for CDMPs in human intervertebral disc. (row A) Cartilage derived morphogenetic protein (CDMP 1) and (row B) CDMP 2. Images are of nucleus pulposus of grade 1 non-degenerate discs (column 1), the nucleus pulposus of grade 10 degenerate discs (column 2) and IgG controls for each antibody. Bars = 570 Âľm.

ples to investigate significant differences in DNA content, GAG content and release into media and aggrecan and type II collagen gene expression.

Results Immunohistochemical localisation of CDMP 1 and CDMP 2 Immunopositive staining for both CDMP 1 and CDMP 2 was restricted to the cytoplasm of native disc cells in both nondegenerate and degenerate discs and there was no statistical significance between non-degenerate and degenerate discs (P > 0.05; Table 2).

Staining was particularly prominent in the cytoplasm of the chondrocyte-like cells of the NP and IAF, with both single cells and those in clusters showing immunopositivity (Figures 1 and 2). CDMP 1 immunopositivity was observed in a higher proportion of cells in both non-degenerate and degenerate discs than CDMP 2 (P < 0.05). A greater proportion of cells were immunopositive for CDMP 1 and CDMP 2 in the NP than the IAF (P < 0.05), and the proportion of immunopositive cells in the OAF was always lower than that seen in the NP and IAF (all targets P < 0.05). No immunopositivity was observed in the matrix of the IVD or in the endothelial cells of the blood vessels for either CDMP 1 or 2.

IgG controls were negative (Figure 1).

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Immunohistochemical staining for BMP RII We have previously shown BMP RII immunopositive staining in the human IVD with a greater number of immunopositive cells within the NP than the IAF and OAF (P < 0.05).

Furthermore, in IVDs graded as intermediate degeneration there was an increase in the proportion of immunopositive cells, which was significant in the NP (P < 0.05)17 Effect of CDMP 1 on proliferation of human NP cells derived from degenerate discs To determine the effect of CDMP 1 on cellular proliferation DNA content per alginate bead was calculated following two weeks of treatment with CDMP. An increase in DNA content (28% increase in CDMP-treated cells v/s untreated cells) was observed in the alginate bead cultures treated with CDMP but this did not reach significance (P = 0.35; Figure 3).

Effect of CDMP 1 on GAG production of human NP cells derived from degenerate discs A significant increase in overall GAG production (i.e. within the CM, FRM and media together) was observed in NP cells derived from degenerate discs treated

with 10 ng/ml CDMP 1 for two weeks compared with untreated NP cells (P < 0.05). An increase in GAG content of CM in CDMP-treated cultures was observed but this did not reach significance (P = 0.43). However, the GAG content within the FRM was significantly increased following CDMP 1 treatment for two weeks (P < 0.05). No difference was observed in the GAG released into the media during the two weeks treatment with CDMP from untreated alginate bead cultures of NP cells derived from degenerate discs (P = 0.24; Figure 4).

Effect of CDMP 1 on gene expression for aggrecan and collagen type II in human NP cells derived from degenerate discs A significant increase in both aggrecan (3831-fold increase) and collagen type II (1660-fold increase) gene expression was observed in NP cells derived from degenerate discs cultured in alginate beads and treated with 10 ng/ml CDMP 1 for two weeks (P < 0.05; Figure 5).

Discussion A major cause of LBP is degeneration of the IVD, of which proteoglycan loss is a key feature and has been linked to loss in disc height, de-stabilisation of the motion segment and the ingrowth of blood vessels and nerves resulting in generation of pain 28,29. Thus a potential therapeutic approach to repair the degenerate disc would be the stimulation of normal disc matrix production particularly increased synthesis of proteoglycans. A number of growth factors have been suggested as possible therapeutic agents. However, our previous study suggested that the addition of growth factors which bound to TGF RII, FGF R3 and IGF RI may also induce unwanted blood vessel ingrowth 17.

However, we demonstrated that growth factors, such as CDMP 1 and 2, which elicit their response via BMP RII, should not induce blood vessel ingrowth.

Here we demonstrate the synthesis and localisation of CDMP 1 and CDMP 2 within human IVDs. Although a small decrease in the proportion of cells within the NP staining for CDMP 1 and CDMP 2 was observed during degeneration this was not significant. Similarly Bobacz and colleagues demonstrated that both

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Figure 2. Assessment of immunopositive staining for CDMP 1 and 2 in human intervertebral discs. Percentage of cells with immunopositivity for (a) cartilage derived morphogenetic protein (CDMP) 1, (b) CDMP 2, according to location in the disc and grade of intervertebral disc degeneration (n = 30). Data are presented as means Âą standard error.* P < 0.05 compared with nondegenerate discs.

Figure 3. Effect of CDMP treatment on DNA content of alginate beads containing NP cells derived from degenerate discs treated with CDMP for two weeks. Data are presented as means Âą standard error. CDMP = cartilage derived morphogenetic protein; NP = nucleus pulposus.

CDMP 1 and CDMP 2 were expressed in normal and osteoarthritic (OA) articular cartilage with no change seen during OA18. This suggests that the pathogenesis of disc degeneration or OA is not associated with a reduced expression of these growth factors.

CDMP has been shown to result in increased proteoglycan production in human mesenchymal stem cells30, a chondrocyte cell line31, and in human articular chondrocytes18,19. Recently, a small number of studies have also demonstrated

proteoglycan stimulation in bovine, rabbit and mouse disc cells21,22. However, to date, no studies have demonstrated an increase in proteoglycan production in degenerate human IVD cells following CDMP treatment. Here we investigated the effect of CDMP 1 on human NP cells cultured in an alginate bead system. Importantly an alginate bead culture system was used as this maintains the in vivo phenotype of IVD cells, which is lost in monolayer culture25,32. Our results demonstrate that cells derived from degenerate human discs can

also respond to CDMP with an increase in GAG production, although our study only used three patient samples. These results confirm those derived from animal disc cells where CDMP resulted in significant increases in GAG production21,22.

The accumulation of GAG within alginate beads was investigated within the compartments: CM and FRM, together with GAG released into media. The majority of the GAG produced by the degenerate NP cells was found in the FRM, and this was the area which showed a significant increase in GAG accumulation following treatment with CDMP 1. The CM is thought to represent the highly structured compartment encircling each cell and corresponds to the combined pericellular and territorial matrix pools which surround each cell in vivo25,33,34. In contrast the more loosely organised compartment known as the FRM, accounting for approximately 95% of the total volume of matrix, is thought to represent the interterritorial matrix compartment in vivo25,34. As this area is thought to account for the majority of the matrix in vivo the fact that more GAGs were found in this area of matrix following stimulation with CDMP is promising for future therapeutic approaches.

The current study also showed that CDMP1 induced dramatic increases in the gene expression for the matrix molecules aggrecan and collagen type II within degenerate human NP cells, as has

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Figure 4. Effect of CDMP treatment on GAG content of NP cells derived from degenerate discs. Data are presented as GAG content of the cell associated matrix, further removed matrix and GAG released into the media per ug DNA (means Âą standard error. * P < 0.05 compared with untreated controls). CDMP = cartilage derived morphogenetic protein; GAG = glycosaminoglycan; NP = nucleus pulposus.

Figure 5. Effect of CDMP treatment on aggrecan and type II collagen gene expression in NP cells derived from degenerate discs treated with CDMP for two weeks.

Absolute quantification of copy number per 250 ng cDNA normalised to the housekeeping gene 18 s. Data are presented as means Âą standard error. * P < 0.05 compared with untreated controls. CDMP = cartilage derived morphogenetic protein; NP = nucleus pulposus.

been reported in mouse IVD cells 22.

During disc degeneration the production of both aggrecan and collagen type II is decreased23,35 leading to reduced hydration and ability to withstand load. Thus, if a growth factor could be applied which can

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successfully stimulate the synthesis of these important matrix molecules this would be of benefit for regenerating the degenerate disc.

Previous studies investigating the effect of CDMP1 on rabbit disc cells in

monolayer 9 and mouse 22 and bovine disc cells in alginate21 have shown significant increases in cell proliferation. Here we showed a small increase in proliferation of human disc cells in alginate culture following treatment with CDMP1 for two weeks, although, possibly due to the small sample size, this did not reach significance. Increases in proliferation could be of benefit in a therapeutic approach as a mechanism to replace some of the cells lost through apoptosis and senescence which are common features during disc degeneration27,36.

Importantly, this study, together with previous animal studies, suggests CDMP could be a useful therapeutic agent in the regeneration of the degenerate IVD and provides supporting evidence for the clinical use of CDMP in human IVD degeneration. Indeed a phase I/II clinical trail has just started investigating the efficacy and safety of recombinant GDF 5 (CDMP 1) injection into the IVD for degenerative disc disease37. However, it must be noted that any proposed therapy may have to target a number of other problems that are associated with disc degeneration. Combinations of factors may be needed in order to promote matrix synthesis and inhibit the increased catabolism seen within the degenerate disc38,39. Furthermore, it has been shown that the nutrient supply diminishes with degeneration, which may also limit disc cell self-renewal and function40. Thus, potential therapeutic growth factors may have to be combined with therapies aimed at restoring disc nutrition or targeted at those patients in which the cartilaginous endplates (through which nutrients are received) are unaffected, that is not calcified, or sclerotic40.

Conclusions Our data demonstrates that CDMP 1 and 2 protein is expressed by both non-degenerate and degenerate discs together with its receptor (BMP RII), suggesting CDMP is involved in the normal matrix homeostasis with the human IVD. Importantly we have demonstrated, for the first time, that human disc cells derived from degenerate discs retain their ability to respond to CDMP and that such treatment leads to an increase in aggrecan

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and collagen type II gene expression and increased accumulation of GAGs. Together this data suggests that CDMP is an important anabolic growth factor in the IVD and could be a suitable therapy to aid in IVD repair/regeneration, via stimulation of matrix synthesis.

Abbreviations AF: annulus fibrosus; BMP: bone morphogenetic protein; BMP RII: BMP receptor 2; BSA: bovine serum albumin; CDMP: cartilage derived morphogenetic protein; CM: cell-associated matrix; DMEM: Dulbecco’s modified eagle medium; DMMB: dimethylmethylene blue; FGF: fibroblast growth factor; FGF R3: FGF receptor 3; FRM: further removed matrix; GAGs: glycosaminoglycans; GDF: growth differentiation factor; H&E: haematoxylin

and eosin; IAF: inner annulus fibrosus; Ig: immunoglobulin; IGF: insulin-like growth factor; IGF RI: IGF receptor 1; IHC: immunohistochemistry; IVD: intervertebral disc; LBP: low back pain; MMP: matrix metalloproteinase; NP: nucleus pulposus; OA: osteoarthritis; OAF: outer annulus fibrosus; PCR: polymerase chain reaction; TGF: transforming growth factor; TGF RII: TGF receptor 2.

Competing interests The authors declare that they have no competing interests.

Authors’ contributions CLM helped conceive the study, participated in its design, performed the majority of the laboratory work and all the analysis and co-wrote the manuscript.

AJF participated in interpretation of data and contributed to the preparation of the final manuscript. JAH conceived the study, secured funding, contributed to its design and co-ordination, participated in interpretation of data and contributed to the preparation of the final manuscript. All authors read and approved the final manuscript.

Acknowledgements The authors wish to acknowledge the support of the joint Research Councils (MRC, BBSRC, EPSRC) UK Centre for Tissue Engineering (34/TIE 13617). The work was undertaken in the Human Tissue Profiling Laboratories of the School of Clinical and Laboratory Sciences that receive core support from the ARC (ICAC grant F0551).

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