AO Dialogue 1|07

AO Foundation

AODIALOGUE The magazine for the AO community

1 / 07

Community zone

Expert zone

AO—strengthening our brand for the future

Implant surfaces: Do they have any relevance to the surgeon?

New corporate identity released April 2007

Research within AO

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Table of contents community zone AO in depth

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AO—strengthening our brand for the future

people

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Sigmund Freud—his oral neoplastic disease and oral, maxillary, and facial surgery Sylwester Gogolewski

events

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AO in Scotland Davos Courses 2006—assessment and evaluation AO Educators’ Seminar for ORP, Davos 2006—a week to remember

news

Research within AO.

Read more in the expert zone.

AO Dialogue May 2007 Editor-in-Chief: James F Kellam Editorial Advisory Board: Jorge E Alonso James Hunter Frankie Leung Joachim Prein Jaime Quintero Pol M Rommens Publisher: AO Foundation Design and typesetting: nougat.ch Printed by Bruhin Druck AG, Switzerland Editorial contact address: AO Foundation Stettbachstrasse 6 CH-8600 Dübendorf Phone: +41(0)44 200 24 80 Fax: +41(0)44 200 24 60 E-mail: dialogue@aofoundation.org Copyright © 2007 AO Foundation, Switzerland

All rights reserved. Any reproduction, whole or in part, without the publisher’s written consent is prohibited.

Great care has been taken to maintain the accuracy of the information contained in this publication. However, the publisher, and/or the distributor and/or the editors, and/or the authors cannot be held responsible for errors or any consequences arising from the use of the information contained in this publication. Some of the products, names, instruments, treatments, logos, designs, etc. referred to in this publication are also protected by patents and trademarks or by other intellectual property protection laws (eg, “AO”, “TRIANGLE/GLOBE Logo” are registered trademarks) even though specific reference to this fact is not always made in the text. Therefore, the appearance of a name, instrument, etc. without designation as proprietary is not to be construed as a representation by the publisher that is in the public domain.

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AO Principles of Fracture Management AOSpine Manual

expert zone

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Implant surfaces: Do they have any relevance to the surgeon?

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Platelet-rich plasma for bone healing—to use or not to use?

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Biotechnology in musculoskeletal surgery: outlook and expectations

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Pelvic and acetabular fractures—past, present, and future

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AO Debate—acute on chronic, unstable slipped capital femoral epiphysis

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editorial

Changes The mention of change always throws fear into most of our hearts.

What we were comfortable with is about to be changed.

James F Kellam Editor-in-Chief james.kellam@aofoundation.org

We ask why someone has done this to us. Life was satisfactory so why are you doing this to me? However, we must recognize that at times change is for the better and necessary. This issue of the AO Dialogue brings to our readers several major advantageous changes within the Foundation.

Firstly, the AO image is in the process of change. All of you are very familiar with the Blue Triangle and Yellow World that form our logo. This logo has important traditional and personal connections to AO and to Davos so to change it has many very important considerations for the AO Foundation. Consequently it was decided not to get rid of it completely but to standardize it so that it will be recognized worldwide and used in a standard fashion. Our President, Christian Van der Werken will outline the reasons for this change and the importance of this change for the AO Foundation.

Secondly, I would like to introduce you to Herwig Daemon, our new head of communications. Communications is a new but very important area within

the AO Foundation. Without a policy or program in communications, we lack the ability to meet the needs of our individuals and stakeholders who are involved with the Foundation, which is you, our readers and you, our course participants. We also lack the ability to promote ourselves throughout the world as an independent academic surgical research and education foundation. Mr Daemon has an impressive background in communication and most importantly has a philosophy of communication that matches the vision and mission of the Foundation. As Editor of AO Dialogue and the head of the AO Communications Advisory Board, I wish to welcome him aboard and look forward to the changes he will bring us.

Finally, in the expert zone there are several articles by our research scientists.

These individuals, Mauro Alini, Geoff Richards, and one of our biotechnology advisors from the AO Biotechnology Advisory Board, David Grainger, are bringing forth changes in how we approach fracture fixation and fracture healing. Mauro Alini reviews platelet derived growth factors and their effect on bone healing. Geoff Richards shows how changes in implant surfaces can modify how the body reacts to the implant. David Grainger provides an overview of the change that biomaterials and biotechnology may have in our future care of musculoskeletal injury and disease.

Once again, although change strikes fear and concern in our hearts, if done well and for the appropriate reasons, it can only make us better as it can for the Foundation.

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A Message from the President

AO—strengthening our brand for the future At the start of April 2007, AO released its new Corporate Identity to the world.

But what exactly is Corporate Identity, and why is it important?

Christian van der Werken President of the AO Foundation chris.vanderwerken@aofoundation.org

Put simply, Corporate Identity is the identity of a corporation or organization which appears in the form of a brand, trademark or logo—usually created within a set of guidelines. These guidelines are crucial because they define how the identity is applied for consistent use: through colors, typefaces, layouts, logical “brand” hierarchy, and so on.

Strengthen, modernize, simplify, reduce

The efforts to create an updated, consistent Corporate Identity for the AO are based on four main goals: • To strengthen the AO brand recognition as well as our worldwide recognition. This is possibly the biggest challenge we face today. With the impact of globalization, it is more crucial than ever to present one face to the world. An easily distinguishable identity also appeals more to its target audience. The AO name and logo are strong, and have been around long enough to prove so. But an attractive logo is not enough—for a brand to achieve recognition, it requires consistency in its use. And that can only happen through having a clear set of guidelines, and adhering to them.

• To modernize the overall AO brand communications appearance. In doing so, we portray ourselves as a modern organization by slightly updating the earlier designs. The AO logo will be modified, with different logo versions for different applications to accommodate a variety of print technologies (Fig 1). We will maintain our existing typography (Formata and Meridien fonts) for familiarity. Our brand colors of blue and yellow will be redefined to strengthen the print quality, and we will use secondary colors for charts, graphics, and a redefinition of imagery and style (Fig 2).

• To simplify the complex AO brand structure that currently exists. Today each institute, region, and section has its own brand design. (see Fig 3) As a single organization, we can consolidate each of those institutes, regions and sections to be recognized as “one AO”.

By simplifying our brand structure, we will achieve one streamlined look for all organizational units within AO and increase brand recognition worldwide.

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Fig 1

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AO in depth

The modified AO logo.

• To reduce costs. A new “one-size-fits-all” concept will involve a consolidation of formats, including the development of a web-based design tool for non-design professionals that is easy to use. Our existing media will be redeveloped, with new stationery (DIN and US formats), newsletters, notepads/forms, literature (brochures—from the annual report to the course programs), presentations, posters, and any other special formats.

Colors

Pantone © 294 C

Pantone © 109 C

CMYK

100/68/7/30

CMYK

Fig 2

The AO brand colors.

0/10/100/0

Sender address structure Roll-out plan

Each AO employee involved in planning, creating, or implementing media will receive a set of guidelines in the near future. I’m looking forward to seeing the effects of this new initiative, and am counting on each and every AO employee to help ensure that these guidelines will be consistently carried out in order to make it a real success.

Organization

Regions

Sections

Specialties

Alumni Associations

AO Foundation

AO East Asia

AO Austria

AO CMF

AO Alumni Association

AO Foundation Research

AO Latin America

AO Switzerland

AO Veterinary

AO ORP Alumni Association

AO Foundation Development

AO North America

AO Germany

AO Alumni Association Chapter Germany

AO Foundation TK System

AO Spain

AO Alumni Association Chapter France

AO Foundation Clinical Investigation

AO UK

AO Alumni Association Chapter USA

AO Foundation Education

AO Alumni Association Chapter Czech Republic

AO Foundation Publishing

AO Alumni Association Chapter Thailand

AO Foundation Research Fund

For addtional information go to: www.aofoundation.org

Fig 3

The modified AO address “tree“.

and more

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Sigmund Freud 1931

1935

His oral neoplastic disease and oral, maxillary, and facial surgery

Prof Nicolas Hardt Clinic for Oral, Maxillary and Facial Surgery, Cantonal Hospital, Lucerne, Switzerland nicolas.hardt@ksl.ch

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Sigmund Freud (1856–1939), the founder of psychoanalysis, developed a carcinoma of the buccal cavity in 1923, which was treated between 1924 and 1938 by Prof Hans Pichler (1877–1950), Professor of Oral, Maxillary, and Facial Surgery at the University of Vienna, Austria. Freud and Pichler were both professors there.

Freud’s neoplastic disease illustrates the development of oncological oral, maxillary, and facial surgery from 1920–1940, and the problems of maxillary resection. It also shows the specialty’s medical and technical developments which occurred in that time period.

This chronicle takes place against the backdrop of the National Socialist dictatorship in Germany and Austria.

Detailed information on Freud’s neoplastic disease is available from two sources. The first is Pichler’s 80-page closely-written case history report, and the second is Freud’s 1929–1939 diary, in which he recorded perceptions about his own health.

The first consultation with Pichler in 1919 was occasioned by painful

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1930

Sigmund Freud at different times in his life.

swelling in the area of the right palate and maxillary tuberosity which had lasted for about a week.

In 1920, an ulcer developed in the same area of the tuberosity, which healed by itself.

Despite being forbidden to smoke, Freud continued to smoke 20 cigars daily. In February 1923, the renewed occurrence of erosion in the area of the right posterior alveolar tuberosity was diagnosed by his treating internist Dr Felix Deutsch as leucoplakia with dysplasia. He was referred to Prof Markus Hayek (1861–1941), Head of the Ear, Nose, and Throat clinic in Vienna.

Prof Hajek undertook a partial local excision in the area of the right tuberosity under local anesthesia.

Postoperation, significant arterial bleeding was stemmed by the attending nurse.

The histopathological examination showed the presence of a squamous cell carcinoma. Freud was not informed of this, and he was referred to Prof Guido Holzknecht (1872– 1931), who applied radiotherapy.

In September 1923, during a journey to Rome, Italy, Freud suffered

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from a major oral hemorrhage, which stopped without treatment.

Once home, he consulted Pichler, who recorded the findings shown in figure 3. Tumor growth was confirmed in the area of the tuberosity, palatoglossal arch, and palate, with involvement of the cheek and mandible.

On October 4, 1923, assisted by Bleichsteiner, Pichler performed a ligation of the right external carotid artery, with extirpation of the submandibular and cervical lymph nodes.

In a follow-up operation one week later, a partial maxillary resection was performed. Covering of the wound surfaces was carried out using the split skin graft technique published in 1917 by Esser (1877– 1976), and by the insertion of a provisional obturator prosthesis. On the evening of the operation, Freud enjoyed two Havana cigars.

Based on the histopathological results (R1 resection), Pichler, assisted by Hofer and Bleichsteiner, performed a fourth operation on November 12, 1923, which comprised further resection of the pterygoid process and a partial resection of the soft palate.

During 1923 and 1924, there were a total of 143 outpatient consultations with Pichler. Three new obturator prostheses were made in this time period.

Between 1926 and 1936 there was a cycle of continually relapsing leucoplakia, nonspecific proliferations, precancerous changes, and papillomas. This led to 122 consultations and 5 further operative interven-

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Prof Markus Hajek (1861–1941).

Findings at the consultation with Prof Pichler in 1923.

Prof Hans Pichler, 1923.

Dr Max Schur (1897–1969).

tions between 1926 and 1928, each comprising local excisions and diathermy treatment. In March 1928, a fifth new obturator prosthesis was inserted.

By 1929 Freud had lost confidence in Dr Deutsch, and Dr Max Schur (1897–1969) took over the followup visits as his personal physician– a total of 49 consultations. Pichler performed no new treatments from June 1928 to 1929.

In 1929, political unrest first became apparent with the raids of Nazi groups on Prof Tandler’s Anatomical Institute, forcing students to flee through windows.

In the fall of 1929, Freud traveled to Berlin for the new construction of obturator prostheses by Prof Hermann Schröder—an oral surgeon at the Charité University Hospital.

In October 1930 there was a clear recurrence at the operation site, leading to an eleventh operation by Pichler with further resection, split skin transplantation from the forearm, and a renewed intraoperative insertion of an obturator prosthesis. The histopathological findings showed precancerous changes.

More relapses occurred in February and April 1931. These relapses were treated by means of electrocoagulation, which had been introduced into surgery in 1930 by Hans von Seemen, a pupil of Erich Lexer.

The recurrence in April 1931 was excised during an additional surgical intervention under local anesthesia. This resulted in major arterial bleeding, and the resected area was covered with a split skin graft. The histopathological results

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again showed Freud’s acceptance the presence of a precancerous of prostheses was lesion. extremely bad, he Freud turned to Prof V Kancalled them, “the zanjian (1879– curse of my life”.

1974) to construct three new prostheses in Hans Pichler’s laboratory. One was made of hard rubber, and two from hard rubber with a palate section made of soft rubber. The cost of these prostheses was US $6,000, and paid for Boston based Kanzanjian‘s European vacation.

Freud’s acceptance of prostheses was extremely bad, he called them, “the curse of my life”.

In 1932, four operations with excisions and electrocoagulations were performed for multiple recurrences. The histopathological diagnosis of cancer in situ continued to be made.

When the Nazis took power on January 30, 1933, Germany not only experienced political changes, but also a power takeover of its clinics. Under an April 1933 law, politically unreliable professors were dismissed from public office (a total of about 15%, up to 30% in Berlin and Frankfurt). Racism played a decisive role in only a third of the professors dismissed (Evans 2000).

This affected 11.5% of all internists, 10% of surgeons, 17% of neurologists, 90% of psychoanalysts and 5% of oral surgeons. At the Charité in Berlin, every third doctor was dismissed (Bleker and Jachertz 1989).

Prof Cohn-Stock (1891–1985), who

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Prof Hermann Schröder of the Berlin Charité.

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Prof Jakob Erdheim (1874–1937).

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Prof V Kanzanjian (1879–1974).

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Obturator prosthesis with detachable palate section.

10 Prof Günther Cohn-Stock (1891–1985) Charité Berlin.

11 May 10, 1933: Burning of books.

performed the first maxillary segment osteotomy in 1920, was one of many who then emigrated.

At the notorious book burning at the University of Berlin on May 10, 1933, Freud was declaimed with the sentence: “against the overestimation of life’s psychological drives which eat away at the soul, and for the nobility of the human spirit. We surrender the written works of the Jew S Freud…”

Compared to the lot of German Jews, Freud considered life in Austria to be like living on an island of the “blessed”. He was under the false impression that anti-Semitism would not find fertile soil in Austria.

Freud in January 1933: “People are afraid that the German nationalistic excesses are going to encroach on our little country. That “People are afraid is nonsense. I that the German do not see any danger here”. nationalistic excesses April 8, 1933: “If are going to encroach the Nazi movement extends on our little country. to Austria, its That is nonsense. course will not be marked by I do not see any the excesses of danger here.” the German

movement, as the Austrians will not become as brutal as the Germans”.

A classical failure of judgment, as resulting events would show.

June 6, 1933: “The world is a huge prison and Germany is the worst cell. It pleases me to think that we are still living as if on an island of the blessed”.

Freud must have known that the elite of German psychiatry passionately supported the Nazis’ laws.

For example, the neurologist and psychiatrist Prof Carl Bonhoeffer, while explicitly against killing by doctors, nevertheless did not condemn the inhuman practice of sterilization (Kater 2002).

In 1934, on the recommendation of Prof Rigeaud of the Institut Curie (Paris) and Prof Schloss (Vienna), a radium prosthesis was inserted.

No further details exist. Further relapses occurred, resulting in three local operative interventions in May, June, and September 1934.

The first signs of political chaos in Austria began with the murder of the Federal Chancellor, Dollfus, by Austrian Nazis on July 25, 1934.

Freud’s health continued to suffer.

In 1935 four operations were performed with the diagnoses: verrucous leucoplakia, papilloma, and precancerous papilloma.

In January and March of 1936, the 26th and 27th operations were performed, with the same histopathological findings of verrucous leucoplakia. In July the 28th operation, the first to be performed not under local anesthesia, but using nitrous

oxide anesthesia and local anesthesia, with the resection of an ulcer in the area of the palate took place.

The histopathological diagnosis showed the presence of a squamous cell carcinoma, 13 years after the first diagnosis. As there were no tumor-free areas in the contours, a 29th operation was performed with follow-up resection, and again in December, another operation under nitrous oxide anesthesia, with coagulation of a new ulcer.

An extreme trismus followed, for which newly discovered short wave treatment was applied.

The 31st operation was performed in April 1937, and no new tumor growth was found. The extreme trismus and pain remained; the maximal mouth opening was measured as 12mm distance between incisor teeth.

The pathologist Prof Erdheim, who had provided almost all the previous histological diagnoses, died at the end of 1937. So great was his involvement in this case that he was able to identify unlabeled sections as belonging to Freud.

In January 1938, a squamous cell carcinoma again recurred in the areas of the maxillary antrum and orbital floor, leading to a 32nd operation under nitrous oxide anesthesia with extensive resection of these regions.

A follow-up resection performed in February showed only leucoplakia.

In March 1938, the Nazis assumed control of Austria. Freud described this as FINIS AUSTRIAE, by which he was referring more to the demise

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12 Prof Hans Pichler 1936.

of the upper middle class of the old Austria than to political change.

Austria’s absorption into the Third Reich marked the beginning of Jewish persecution, and thus of Freud. Using the 1935 Nuremberg racial laws, 28 professors and 120 university lecturers were dismissed from public office.

Austrian Nazis enthusiastically assisted the German anti-Semites.

This was based on a racism that had a stronger tradition and deeper roots in Austria and Hungary than in Germany (Carsten 1976, Kater 2002). By the spring of 1939, almost 2,000 Jewish doctors in Austria were forced to give up their profession.

In spite of his neoplastic disease, Freud, then 82, decided to emigrate but was unable to obtain an exit permit, as the Nazis already regarded Freud as the personification of the Jewish enemy.

Faced with this situation, Pichler managed to convince Dr Sauerwald—the party commissioner responsible for exit permits—that Freud’s scientific works were not concerned with “Jewish villanies”, and he succeeded in getting Sauerwald to study Freud’s writings.

Sauerwald then suppressed all incriminatory documentary evidence against Freud, while Pichler dealt with the secret police. Freud left Vienna on the Orient Express on June 4, 1938.

Before departure, a last examination was carried out by Pichler on June 2, 1938, who detected no recurrence of the tumor.

During an examination in London in July 1938, Dr Exner, a South African oral surgeon who had previously been a guest of Pichler, could also find no tumor; although Schur was convinced that a recurrence of the tumor would occur.

Pichler flew to London on September 7, 1938, and his examination showed an extensive recurrence of the carcinoma with extension to the right orbital floor. Surgery took place on September 9, 1938, using the McIntosh intubation technique that had not yet been introduced to continental Europe. A cheek flap, using the method of Moure (1922), was performed and an extensive right-sided resection of the maxilla and orbital floor with concomitant intraoperative instantaneous section monitoring. This was also not in use on the Continent.

The diagnosis using instantaneous sections showed an R0 resection, ie, tumor-free resection edges with the histopathological diagnosis of a verrucous leucoplakia. A renewed tumor growth in the orbital floor area occurred in February 1939.

The sample excision confirmed the presence of a squamous cell carcinoma. Prof W Trotter and Exner described the tumor as inoperable.

Pichler wrote to insist on an additional operative intervention.

On the advice of the treating doctors, x-ray irradiation was performed by the radio-oncologist Dr Finzi.

As was to be expected, a necrosis with perforation occurred in the area of the right cheek, which led

13 Nitrous oxide anesthesia 1936 Munich University.

14 Pogrom in Vienna 1938.

15 Departure on the Orient Express ViennaParis-London. Princess Marie Bonaparte, American ambassador Bulitt.

16 Insufflation anaesthesia 1940 using the method of McIntosh.

to unbearable pain. In one of his last letters, Freud wrote on July 5, 1939: “My world is a small island of pain floating on an ocean of indifference.“ Sigmund Freud fell into a coma on September 21 and died at 3am on September 23, 1939.

Summary

Prof Pichler’s treatment of the 14 year long neoplastic disease enabled Freud to create his impressive later works. Thanks to the skilful intervention of Pichler, Freud was able to leave Austria for Britain and thereby avoid the fate of many of his compatriots.

Max Schur, the doctor and poet, wrote the following in 1972 about Prof Pichler: ”He was an exceptionally kind-hearted and human person. A surgeon who was not afraid of performing radical interventions when they were necessary. His association with Sigmund Freud was one of extreme respect, tact, and politeness. Pichler was fortunately a man of obsession, in the best spiritual meaning of the word.”

Bibliography

Literature in the author’s possession.

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Erich Schneider Director AO Research Institute erich.schneider@aofoundation.org

Professor Sylwester Gogolewski is a well-known figure to many within the AO. He has worked on bioresorbable polymers in the AO Research Institute for the past 18 years. After a long career spent mostly in the world of research, this knowledgeable man whose vim and vigor belies his age, has left Davos and the AO to return to his home country.

Sylwester was born in 1936 in Warsaw, Poland.

He received his Master’s Degree from the University of Lodz, where he specialized in chemistry. His doctoral dissertation dealt with nylon, a modern polymer at that time and his habilitation with the crystallization of polyamides. Moving up in his academic career, he became Associate Professor and Head of the Polymer Department at the Technical University of Zielona Góra. 1980 was the year he made Western Europe his permanent home and became a Visiting Professor at the Department of Polymer Chemistry in the University of Groningen, the Netherlands. Even though he only stayed there for three years, his work on vascular prostheses and polyurethanes carried out in this institution inspired him again and again throughout the years. In August 1983 he decided to leave the university to join a Swedish research and development company in the French speaking part of Switzerland. He joined the AO Foundation in 1988 with the task of researching and developing resorbable materials for use in fracture treatment.

During his time within the AO organization, he first studied polylactides as candidates to replace internal fixation devices. He soon realized that constructs made of this material may also serve as bone substitute materials, and that membranes and scaffolds were most valuable for tissue engineering purposes. In great detail, he investigated and developed different composition, manufacturing, and sterilization processes to make sure the materials fulfilled their function in the human body. In later years in Davos, his attention turned again to polyurethanes, another bioresorbable material, which can be tuned to provide optimal conditions for bone as well as cartilage tissue engineering. He not only conducted excellent research, but had his own and his team’s work published in renowned, peer reviewed journals. No less than 150 publications were the result of his tireless work and maybe twice as many abstracts were presented in the leading orthopedic and biomaterials meetings. He was active right up until the end of his career at the AO. Indeed, two of his final projects on isosorbide-based biodegradable polyurethanes and the use of various plant polyprenols to biolize biodegradable polymeric scaffolds to promote cell attachment, growth and proliferation, and/or to prevent tissue adhesion may yet yield great rewards.

Sylwester Gogolewski On his retirement, a tribute to his contributions to the AO.

Prof Gogolewski provided his excellent knowledge of the chemistry, synthesis, and production of resorbable biomaterials as well as their behavior in the human body freely to everyone interested in this subject. This knowledge allowed him to realistically assess the potential of a future treatment option. He has been a cornerstone of the AO Research Institute for 18 years and contributed greatly to our expertise in this area. I sincerely thank him for his innovative work and tireless dedication and wish him a long and happy retirement.

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AO in Scotland

Chris Oliver Consultant Trauma Orthopaedic Surgeon Edinburgh Orthopaedic Trauma Unit cwoliver@rcsed.ac.uk

The 4th Scottish AO Principles of Operative Fracture Management Course for Surgeons was held in March 2007 in Edinburgh. The four day course was held at the new surgical skills centre, Quincentenary Hall (www.surgeonshallcomplex.com) at the Royal College of Surgeons of Edinburgh (www.rcsed.ac.uk). The Quincentenary Hall is a new state-of-the-art surgical skills complex in a versatile modern building adjacent to the historic Surgeons’ Hall. The course chairmanship was taken over by Mr Clark Dreghorn (Glasgow) and Mr Andy Kent (Inverness) this year, replacing Mr Chris Oliver and Mr John Keating from the Edinburgh Orthopaedic Trauma Unit who have led the course since its inception in 2004. The faculty is mostly Scottish with surgeons from Edinburgh, Glasgow, Stirling, Paisley, Aberdeen, and Inverness. On this occasion Dr Maarten van der Elst came from the Netherlands as visiting faculty. The course now caters for 48 participants of which half come from Scotland. The AO Principles Course in Scotland has not only allowed the participants to develop skills but has also allowed the Scottish surgeons to become a cohesive force in trauma orthopedic surgery. The high standard of the Scottish training workshops, lectures, and discussion groups has been internationally recognized.

Edinburgh has a long and distinguished history in medicine and surgery, with many advances pioneered in the city or by Edinburgh graduates.

Notable surgeons include John Hunter, anatomist and “founder of scientific surgery“ in the late 18th century; Robert Liston, who performed the first operation under anesthesia (ether) in 1846; and Sir James Simpson, who discovered chloroform the following year, by testing it on his dinner guests until they slid under the table!

Other “firsts” include Charles Bell, who identified the nerve functions in 1811 and founded the science of neurology; James Syme, pioneer of plastic surgery; the first hypodermic syringe (Alexander Wood 1853). In the early days, anatomy students had difficulty obtaining sufficient subjects for dissection, and the need was filled by grave robbers—the “resurrectionists”.

In 1829 Messrs Burke and Hare streamlined the process by murdering and then selling their victims directly to the unquestioning university‘s surgical department. The pioneering trail continues through Alexander Fleming, discoverer of penicillin (1928) and anti-typhoid vaccines, the UK‘s first successful kidney transplant (Michael Woodruff, 1960) and the cloning of the famous Dolly the Sheep (Ian Wilmut, 1996).

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Davos Courses 2006

Assessment and evaluation Piet de Boer Director AO Education DĂźbendorf, Switzerland piet.deboer@aofoundation.org

Assessment of a course and evaluation of individual presentations within that course is a complex and controversial area. Everyone is agreed that the purpose of AO Education is to improve the quality of care given to patients by the course participants after the course. We are probably several decades away from being able to measure this effect, but the Davos Courses in 2006 were a landmark in our progress towards this goal.

Davos 2006 saw two new programs rolled out for the first time—needs assessment and the Audience Response System (ARS) based course evaluation system.

Needs assessment

This is the brainchild of Bob Fox and Joe Green, our US based educational consultants. The project began following an AOEB brainstorming retreat at the triennial Alumni event in Sardinia in 2005. Individual course chairmen around the world were asked to define key competencies for the courses that they were running. A competence is something that you wish the course participants to acquire as a result of the

course. Twelve competencies were defined for the Principles course and twelve for the Advances course. For the principles course, a different group of course chairmen were asked to write a series of questions with yes/no answers, relating to the competencies that had been defined, to be able to assess the knowledge level of the course participants before the course began.

Course participants were contacted online some four weeks before the course and asked to look at the competencies that had been defined for their course. They were asked to evaluate how important each of these competencies were on a scale of 1–5 and to record how well they thought they already understood these competencies. The difference between the two scores reflected a measure of how motivated the course participants were. Clearly if a course participant has a high perceived need for a given competence and thinks that he has a low level of current knowledge then that course participant will be extremely motivated to learn. Following completion of this perceived needs assessment, course participants on the Principles course were then asked a series of

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yes/no questions relating to the individual competencies. Analysis of these results gave an understanding as to the current level of knowledge of the course participants.

Perceived needs—participants fill in: D

Desired level of competence (1–5)

P

Present level of competence (1–5)

Following the course, the course participants were asked to fill in the same needs evaluation form and to complete a set of questions relating to the competency.

Results

The results of the perceived needs of the course participants from Davos closely reflected those of course participants in Leeds, Sapporo, Reno, San Diego, Stockholm, and Dubai. Overall, course participants were extremely highly motivated and it is interesting that they rated the importance of the individual competencies quite consistently. The need to assess and treat a haemodynamically unstable pelvic fracture in an emergency situation was rated by all course participants, outside Japan, as being the most important skill they could acquire from the Principles course.

Assessment of the yes/no questions showed that approximately 60% of the course participants got the question right and 40% wrong. This reflects the relatively junior nature of our Principles course participants in Davos and this data is similar to that collected in Leeds and in Uruguay.

Following the course, the perceived needs of the course participants dropped dramatically. That is to say that the course participants assessment of the course was extremely favorable. Disturbingly, the results from the yes/no answers however showed virtually no change. We are, at present, working with colleagues from AO North America to change the knowledge assessment tool to a more sophisticated system, to try to better assess the true level of knowledge of our course participants.

The significance of these results is two fold.

Firstly, we have shown that this system can be made to operate reliably and provide reproducible results. Secondly, because AO now possesses and uses such a system we can truly say to any CME authority that the contents of our courses are determined by the needs assessment of our course participants—the highest level of quality as dictated by the CME regulating authorities.

Furthermore, the results with regards to the perceived needs of our course participants will help determine the future structure of courses.

Audience Response System

ARS based course evaluation of individual presentations was carried out on all AO courses this year. Course chairmen were asked to define five key learning objectives for their courses. Course participants were asked at the start of the course how important these were to their everyday practice. At the end of the course, course participants were asked about these key learning objectives. They had five choices: 1. Did not learn anything new.

2. Learned something new, but do not want to use it in my practice.

3. Learned something new, but probably won’t be able to use it in my practice.

4. Reconfirmed that what I do in my practice setting is appropriate.

5. Learned something new and plan on using it in my practice It can be seen that answers 4 and 5 represent a very positive learning experience from the course.

How to read gap values: ≥3

Fear

1.6–2.9 High interest & motivation ≤ 1.5

Low interest & motivation

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At the end of each lecture, discussion group, and practical course, participants were asked to evaluate the presentation. They were asked to evaluate the presentation on a scale of 1–5, as to whether the presentation had been relevant to their practice. They were then asked to evaluate the performance of the individual faculty member concerned in the presentation.

formance could be gauged by their performance scores and also by the difference in the scores between the relevance scores and the performance scores. In the future, we hope to be able to analyze conspicuously good or less than average performance and provide advice to the individual faculty member as to how to improve their own performance.

Results

Overall, the amount of information that we have gained about the Davos 2006 Courses is huge.

Well over a quarter of a million pieces of information were collected and evaluated and the results give us the most comprehensive view of the success of Davos in 2006. This program will continue in the years to come and allow us to get an understanding of how things are changing and hopefully improving with the years. Individual course chairmen now get useful information with regards to planning of future courses and individual faculty members get, for the first time, an objective assessment of their own particular performance. Future developments will include the refining of the question and answer section of the needs assessment and an introduction of this into the Advances courses. We hope that in 2007 a more detailed needs assessment will be able to be carried out for certain other courses including the orthopedic geriatric course.

The results with regards to the five key learning points for the courses showed that most courses had been overwhelmingly successful in achieving their learning objectives. Particularly successful courses were the Swiss Residents’ course held the first week in Davos and the English Principles course held in the second week.

Most courses were extremely well rated by the course participants. However, comparison of the individual courses did show that some courses were consistently more successful than others with regards to the course participants’ assessment. This information was fed back to the course chairmen and individual faculty members and will form a basis for the reevaluation of individual courses in the future.

The data with regards to the individual presentations revealed a hitherto unknown fact. If an individual presentation was rated by the course participants as not being relevant to their practice, then the course participants almost invariably rated the performance of an individual faculty member as being poor. The correlation between these two figures, which has never been recorded before in education research literature, will form the basis for further studies.

Individual faculty were given information with regards to their own particular performance, but were not given information about others.

The assessment of their own per-

The next development in assessment will be the introduction of a research project entitled “The Barriers Project”. The barriers project attempts to look at the barriers that exist for surgeons who wish to change their practice but are not able to do so. A pilot project carried out in 2005 revealed that over 75% of the Advances course participants were unable to change their practice—even if they wanted to—the most common reason being an inability to access or afford the equipment. This research project was approved by the AOEB at its March meeting and preliminary results should be available in early 2008.

The barriers project takes us another small step towards the end process of evaluation of our educational events—evidence that we change the practice of surgeons so as to improve the results of patient care.

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events

A week to remember AO Educators’ Seminar for ORP, Davos 2006

Yvonne Murphy Registered Nurse Birmingham, United Kingdom yvonne.murphy@vhb.nhs.uk

A group of 22 ORP educators from England, USA, Australia, New Zealand, Austria, France, Germany, Belgium, Norway, Sweden, Switzerland, Mexico, Brazil, Israel, Iran, Malawi, and China gathered at the 6th ORP Educators’ Seminar, in Davos, in December 2006 for an advanced learning experience. The seminar’s aims were to support the ORP in acquiring and developing educational skills in order to contribute effectively to the AO education program within their country and worldwide and to extend and develop the AO ORP Alumni community. Faculty members for this seminar included Susanne Bäuerle, Rossanna Fornazzari, Lisa Hadfield-Law, David Pitts, Donna Russell-Larson, and Isabel Van Rie. Most of the course participants arrived on Saturday, December 9, and stayed in the same hotel allowing everyone to meet and bond almost

instantly. The first meeting of the participants occurred at the hotel dining room where one long table was reserved for the ORP. Participants introduced themselves as they arrived and everyone felt very welcome and comfortable. This was the start of a group friendship that went from strength to strength.

The course began early Sunday morning as the group met at the hotel reception and were introduced to some of the course core faculty. The welcome meeting for the entire surgical faculty was held at the conference centre. I was astounded at how many faculty members it took to run the courses in Davos. The room was enormous and almost full. The President of the AO Foundation, Chris van der Werken, welcomed everyone with an inspiring talk as did Piet de Boer, the Director of AO Education.

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Our group’s first task was to observe the Principles precourse meeting.

We were asked to identify three items we had learned from this observation. Although we all could certainly identify more than three items that we could use in our own precourse meetings, it was evident that a clear course plan of action, review of the practical exercises, and the opportunity for faculty to discuss their concerns were the most important items. Our group was made to feel very welcome by the surgical faculty and we were encouraged to introduce ourselves alongside our colleagues.

After the precourse meeting, the group separated to do different things including lunch, going back to the hotel to rest etc. I was in a group of five that chose to attend the Synthes welcome get-together on Jakobshorn Mountain. This was an amazing experience for me as I Participants enjoying both the Davos weather and the seminar. had never skied or been on a snow covered mountain before. The trip up the mountain made me a little nervous when I realized how high up we were going, but once there I wouldn’t have missed it for anything. The sun was shining yet it was snowing and the snow looked like glitter falling from the sky. In the midst of this there was a barbeque, music playing, and mulled wine to keep out the cold. It was a fantastic atmosphere and just one of the many wonderful memories I will take from Davos and keep with me always.

In the evening we returned to the conference centre for the main welcome reception. After the welcome we attended a dinner to meet the course directors and core faculty who would be facilitating the ORP educators’ seminar. This was another great learning experience. Everyone shared stories about their countries and how courses for ORP were organized in each one, as well as generally getting to know each other.

This was the first of many dinners together.

Monday was the first day of our seminar. The president of the AO Foundation spoke about

the importance and value of ORP in AO education. Following this, we went on to examine the reasons we had come to the educators’ seminar.

Typical answers to this question included, “Be able to give presentations and feel confident in doing this”, “Develop my teaching skills”, “To gain knowledge and ideas to take back to my own courses”, “Share ideas and meet people”. We heard a talk about valuing our differences. The ORP faculty who travel to present courses in different countries spoke to us about the different cultures and how doing and saying something one way in one country may not be acceptable in another, and how this needed to be recognized and overcome in order to deliver a good course for participants.

After observing a practical exercise involving surgeons we were asked to identify three items that had gone wrong. It was a fantastic learning experience for our group. We went away with the knowledge of what can go wrong even with the best planning and realized how important singing from the same song sheet is. I also think the course director learned from us that day as I know the constructive feedback was available for him to see.

Finally we learned about presentations, the one area where everyone seems to lack confidence.

We learned that “Proper preparation and practice prevents poor performance”. This includes set, dialogue, and closure, and keeping slides clear, concise, and simple. We also learned to integrate questions to make it interesting and to ensure that the participants are awake!

Tuesday was another full and exciting day about teaching and practicals. Developing the roles of a table demonstrator and practical moderator require guidance and support, and this seminar was the ideal place to get it. After preparing and running a practical, feedback was then given to us by our observing faculty.

The day did not finish until late into the evening, as we had been given the task of preparing a presentation for the following day on what we had learned so far. It was a particularly difficult task for my friends who did not have English as their first language. However, it brought the whole group together even more and created a strong bond between us. Everyone helped each other in

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whatever way they could. It was hard work but extremely rewarding.

Wednesday was “the performance”. This was a day full of anxiety for us all, even though we knew we were presenting to our friends. Needless to say it was a successful day full of emotion as we all wanted everyone to do well. Those without English as a first language did particularly well. I am English and I understood every presentation as they were all superb. The presentations were videotaped and we have a copy to look back on and learn from. The seminar from this moment on seemed much more relaxed for all of us as we felt that we had dealt with our biggest challenge, although the hard work and long days continued.

The day finished with us learning about managing a discussion group. This type of learning I particularly enjoy as I find talking to different people easy. Others in the group found it more difficult as it was not a familiar environment for them and one not commonly used in their country. It was, however, something everyone wanted to try once they had learned the principles.

At the end of the day we had a wonderful course dinner where we were taken by horse and sleigh up a mountain to a traditional Swiss restaurant and ate to our hearts’ content.

The seminar topics inspire discussion.

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On Thursday we found out about the AO Foundation and how it works. We were informed about the ORP Alumni and this now made sense to us, we could see what an excellent group this was for ORP education. We explored the AO website.

Exploring this was another wonderful learning experience. I don’t think any of the group realized how much information could be accessed via this and we were all really enthused.

On Friday, we made the link between the research lab and the patient. The process that the products have to go through before approval is quite daunting and extremely interesting. It made me appreciate why implants cost as much as they do. We were also given a practical to do as participants. This was a really exciting experience for me as it was a tibial nailing and I specialize in maxillofacial. With the experience came the realization that teaching and learning principles are just the same whatever the size of the implant.

Finally the seminar came to an end and we reflected on what we had learned and what we would do with it. We had all learned a great deal and knew we had a lot to offer our home countries. On my return home I made a list of words that summed up this seminar for me: inspiring, excellent, interesting, networking, collaboration, realization, development, education, encouragement, humor, laughter, and above all, friendship.

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AO principles • •

•

•

AO Principles of Fracture Management Second expanded edition Thomas P Rüedi, Richard E Buckley, Christopher G Moran For addtional information and to order go to: www.aopublishing.com

For more than forty years, the AO has—true to its calling—imparted the principles of fracture management by several publications and special courses worldwide. The second edition of the AO Principles of Fracture Management book has been fully updated and extended to describe the latest techniques and covers the complete content of the AO Principles Course of today. It is now published as a two-volume set and provides excellent guidance and expertise, compiled by nearly one hundred contributors, all of whom are renowned surgeons and members of the AO faculty. An exceptionally large number of new illustrations as well as animations and video clips turn this work not only into excellent reference books but make them unique learning tools. Both residents as well as advanced trauma surgeons will benefit from this concept.

Fracture reduction and fixation to restore anatomical relationships.

Fracture fixation providing absolute or relative stability, as required by the “personality” of the fracture, the patient, and the injury.

Preservation of the blood supply to soft tissues and bone by gentle reduction techniques and careful handling.

Early and safe mobilization and rehabilitation of the injured part and the patient as a whole.

Volume 1 focuses on the basic knowledge and

the principles of fracture management, eg, biomechanics, tools for preoperative planning, softtissue management, different methods of reduction and fixation, implants. Simultaneously, it addresses new issues pertaining to internal/external fixation, damage-control surgery, minimally invasive surgery, and biotechnology.

Volume 2 focuses on the management of specific

fractures in different anatomical areas. For each of these areas there is a separate chapter discussing the assessment of injuries, surgical anatomy, preoperative planning, surgical treatment, and postoperative care, while pointing out pitfalls and complications. New fixation techniques and implants have in particular been taken into account.

DVD-ROM for PC and Macintosh

• All illustrations are available for download and can be used for personal presentations.

• Animations and video clips featuring step-bystep procedures can also be downloaded for self-education or use within personal presentations.

• The complete text of the book is available for quick reference.

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news

AOSpine Manual Principles and techniques (Vol 1) Clinical applications (Vol 2) Max Aebi, Vincent Arlet, John K Webb For addtional information and to order go to: www.aospine.org

Max Aebi, Vincent Arlet, and John K Webb are the three editors-in-chief who oversaw the creation and publication of this book along with a team from the AO. More than 80 authors contributed to the manual and the twelve section editors ensured high standards throughout.

The two volumes offer the reader a combined total of 1,500 pages and over 3,000 figures. Also included is one DVD-ROM for both volumes.

Principles and techniques (Vol 1) relates to the teaching of basic surgical knowledge and surgical techniques at AOSpine courses and acts as a foundation for the application of these principles in clinical practice.

It presents basic scientific and technical principles—it provides the reader with the scientific background to understand spine surgery and it teaches how to apply these surgical principles using the instrumentation necessary in a stepby-step manner with exceptional illustrations; some critical steps are explained using sequences from AOSpine teaching videos.

Clinical applications (Vol 2) is based on the novel interactive sessions within AOSpine courses and acts as a huge resource of clinical cases with which the readers’ current knowledge on how to treat their patients can be expanded.

It presents discussions concerning typical clinical cases. The reader is involved in the development of the rationale of treatment, the indications, the contraindications, the argumentation in favor of a technique or against one, and the outcome.

Case examples are outlined with learning points from more than 50 surgeons of which each is a leader in their surgical field. Clips from AOSpine live surgery videos enhance the learning experience.

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R Geoff Richards

Implant surfaces: Do they have any relevance to the surgeon?

What happens when an implant surface is placed into the body? When inserting a plate, nail, screw, cage, or any other

internal fracture fixation (IFF) device into the body, regardless of the material, the implant is coated almost immediately (within seconds) with a proteinaceous film upon contact with blood. The proteins come from the blood and provide a provisional matrix for the cells to adhere to. The cells never see the actual implant surface but this matrix which has adsorbed to the surface. The surface can determine which proteins absorb and the orientation of their attachment. Cell adhesion then usually follows within minutes (fibroblasts and macrophages) followed by either soft-tissue adhesion or matrix adhesion and eventual mineralization.

The molecular events at the surface-body interface are controlled by surface properties. In an example of a metal used in IFF (Fig 1), the actual surface is not the metal but a continually changing oxide surface. Metal ions diffuse at different rates into the oxide and oxygen diffuses from the oxide into the bulk metal. Biological ions are incorporated onto the oxide along with protein adsorption. The proteins undergo confor-

mational changes over time. All these processes are influenced by: surface topography, greater texture exposes more discontinuities for interaction with proteins; surface chemistry, determines types of intermolecular forces, governing interaction with proteins; surface hydrophobicity, determines which and how much proteins bind; surface heterogeneity (nonuniformity), different domains interact differently with proteins; and surface potential, influences the distribution of ions in solution and interaction with proteins. The protein size, charge, and stability affect both the rate of arrival to the surface and interaction with it. Blood (which has more than 150 proteins) interacts with the surface with albumin being the most concentrated, having a moderate size (66KD) dominating initial interactions. Fibrinogen (340KD), which has a lower concentration in the blood has a rate of arrival at least one hundred times slower, but usually dominates the surface, exchanging with the faster and weaker bound albumin due to its greater affinity. This is a very simple view of protein interactions with a surface, but gives an idea of the dynamics of the biological interactions.

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ta lions

Metal/oxide ion diffusion

Ca Biological ion incorporation P

Protein absorption

Protein conformational changes

Fig 1

An implant surface is never static within the body and undergoes continual changes over time, even without mechanical abrasion.

What happens at a soft tissue–implant surface interface?

Internal fracture fixation (IFF) implant surface finishes vary from electropolishing of stainless steel to microrough commercially pure titanium (cpTi) and Titanium-6%Aluminium7%Niobium alloy (TAN). TAN is used in LISS plates, locking screws, and nails and is often mistakenly referred to as titanium by surgeons. In the context of soft tissue, represented in vitro by fibroblasts, members of my group found rough verses smooth titanium and steel does not significantly affect fibroblast cell adhesion or subsequent growth. Polished TAN also promoted fibroblast cell adhesion and growth; however both aspects were seriously compromised on microrough TAN. Specific aspects of the TAN topography were implicated (rough beta phase particles within the softer alpha phase matrix), however, the contribution of its unique surface chemistry to the cell behavior was unknown. The observation of lower adhesion, spreading, and growth on the surface of standard microrough TAN necessitated the design of a series of experiments to help distinguish between the effects of material and those of topography. Coating the standard test materials with a uniform chemistry provided a practical model to investigate how surface chemistry and the various topographies interact in their effect on cells. These experiments eventually drew to the conclusion that behavioral cues for fibroblasts on metal implant surfaces were generally confined to the influence of surface topography over the cue of surface chemistry.

Soft tissues, which are more sensitive to differences in implanted materials than bone, can react much quicker to problematic surfaces and are therefore good biocompatibility models. Early soft tissue integration with vascularization at the

tissue-implant interface, without liquid filled capsule formation is often desirable. If a bone is fixed subperiosteally and the implant is not integrated fully, movement between the implant and tissue interface may cause the formation of a fibrous capsule around areas of the implant which may become liquid filled. Liquid filled soft tissue fibrous capsules are not desirable, as they prevent tissue integrating with the implant and encourage infection because they may reduce vascularization at the biomaterial tissue interface causing the creation of an immunoincompetent zone and an ideal place for pathogen proliferation. Consequently, immune cells are less able to defend the body against any bacteria that have entered at the biomaterial tissue interface. Movement of the implant also influences fibrous encapsulation and may hinder fast integration into the body and also attract more inflammatory cells to the site.

Where gliding tissues are concerned, it is thought that a nonadhering fibrous capsule on the soft tissue side of an IFF implant may reduce the chance of gliding tissues —such as muscles and tendons—adhering to the implant. One example that requires neighboring tissues to freely glide over the implant is within orbital fractures where connective tissues should glide freely and not adhere to the implant surface, or problems with eye movement can occur. In the case of overlying tendons in distal radius fracture treatment, current literature describes how titanium and its alloys tend to lead to more intratendon inflammatory reactions when compared to steel, leading to tendon-implant adhesion, tendon damage which prevents normal tissue motion and may cause limited palmar flexion, and even tendon rupture. The intrusion of a plate can produce

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Fig 2

Scanning electron microscope images of

S aureus bacteria adhered to a) standard microrough TAN, The bacteria are scattered all over the surface in small clumps of 6 bacteria, b) electropolished TAN. Bacteria are found to clump in large clumps, with no small clumps of 6 or less seen.

friction for the gliding tissue and is liable to become a site for tissue adhesion and inflammation. These osteosynthesis applications require the development of surfaces that prevent soft tissue attachment and irritation, allow tissue gliding, but maintain their biocompatible properties. It is highly unlikely that a liquid filled void could occur within these situations, due to the large movements of the gliding tissues. One way to reduce the tissue adhesion would be to reduce surface microroughness of the plate in contact with the tissue. Our work strongly indicates that the surface topography of the titanium (or even titanium alloy such as Ti15MO, used in hand surgery), rather than the material itself is responsible for this problem and polishing of the surfaces of plates in contact with gliding tendons could prevent it. X-ray photoelectron spectroscopy results showed that the surface chemistry of anodized polished metals (titanium and its alloys) did not differ from the chemistry of the standard (as used in clinics) microrough metals. Therefore, the polishing method tested should be suitable for clinical use, where soft tissue adhesion is not desired.

Bone

With long term or permanent implants, such as spine cages or chondylar plates in CMF, osseointegration is vital to their success. Bony integration is increased on implant surfaces with higher amounts of microroughness and this is also seen in the areas of prosthetics (hips and knees) and dentistry (stents). The majority of research within these areas is into increasing bony integration.

IFF devices are often removed to avoid: growth disturbances in pediatrics; delayed infection; implant migration/breakage; allergic reactions; soft tissue irritation; implant protrusion/intrusion (eg, into a joint); build up of fretting particles in unrelated organs (from loose multi component implants), as well as being cosmetically disturbing (protrusion under skin). The necessity of IFF implant removal is chiefly within the pediatric population. Advocates of life long retention maintain that difficulty in removing a device due to extraosseous formation warrant their preservation to avoid complications such as increased operative time, blood loss, and debris contamination.

Problems associated with excessive bony overgrowth account for ~7% of all complications encountered. In temporary implants such as plating, nailing with the use of screws or the application of external fixators, minimal bone bonding to implants is desirable for the least traumatic explantation. Strong bony integration is a disadvantage when considering removal and the surface microstructure is the major determinant of this.

Our in vitro work with osteoblasts has shown that surface polishing acts on a cellular level in that implant surface topography influences both osteoblast proliferation and differentiation. We have shown that surface polishing can significantly reduce expression of osteocalcin, a principle factor involved in bone mineralization, thus essentially inhibiting the cells ability to mineralize and form a mature matrix. Moreover, an inverse relationship has been observed between osteocalcin gene expression and total DNA content, indicating a less differentiated osteoblast phenotype to be present on polished smooth samples. The polishing therefore reduces subsequent mineralization which shows that there is more to surface polishing than simple macro changes for friction of surface roughness on the bony integration.

Our recent in vivo work assessed the effect of surface topography of TAN and titanium (cpTi) screws with different surface topographies (polished and microrough) in a sheep cortical (tibial) and cancellous (rib) bone model over three time periods of 6, 12, and 18 weeks. The effect of implant topography on bone adherence was evaluated mechanically by measurement of the peak torque removal force and histologically to assess the amount of bone present at the surface of the implant. The results demonstrated that polishing both cpTi and TAN resulted in lower removal torque than standard microrough screws when placed into cancellous bone. Polished cpTi screws also had a lower removal torque when implanted in the cortical bone. Polished TAN screws did not have a significantly reduced removal torque when implanted in the tibia but at 12 and 18 weeks, there was a trend for a reduction in removal torque. Histologically, the polished screws consis-

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tently demonstrated a lower percentage of bone contact than the standard microrough implants. This study demonstrates that polishing can reduce removal torque and the percentage of bone contact in vivo and thereby improve the ease of removal of TAN and cpTi screws placed into cortical and cancellous bone. Where nonpermanent implants are concerned, having some fibrous material present (as in the case of these polished cpTi and TAN screws) may be advantageous—because it can prevent the screw from becoming completely overgrown by bone, allowing for easier removal without compromising its stability within the bone (which is based upon thread design more than surface structure).

Current in vivo work in our group looks at locked-screw and plate combinations since many removal problems have been noted with various designs of such systems. TAN is commonly used for screws (and plates with LISS) with cpTi being used for the LCP plate. We believe that excess bone bonding to these implants is the major cause of the difficulty in removing the screws from the plates. The purpose of the study is to assess the effect of surface treatment of LCPs upon direct bone contact after 6, 12, and 18 month implantation times in sheep tibial cortical bone. We anticipate that the polished surfaces will demonstrate decreased bone bonding and decreased extraction forces. The results of this investigation could have significant impact on the surface design of locking-head screws and LCP plates to avoid the clinical problems during removal of the implant. A second area we are working on is intramedullary nailing. IM nails are composed of either stainless steel or TAN. TAN is preferred due to its better biocompatibility and mechanical properties. However excess bone bonding to the TAN nails, resulting in difficulty in their removal has been described. TAN has a microrough surface since the alloy is a mix of soft Îą and harder Ă&#x; phases which gives a micro spiked morphology after surface processing. This surface integrates extremely well with bone (as shown in our previous work with cortical screws in vivo and discs in vitro). We know that polishing TAN smoothes these micro spikes within the TAN surface, which should reduce the amount of direct bone contact for the nails as well as removal torques. The difficulty in removing nails due to excess bone on-growth has not been described for steel, which is clinically used with a smooth surface. After a 12 month implantation period the nails will be extracted by a pull-out test and some nails will remain in situ for histomorphometric evaluation. We anticipate that the polished TAN nails will demonstrate decreased bone bonding and extraction forces. This finding could be used to recommend changes to current surface treatments of intramedullary nails to reduce complications seen with nail removal, especially in rapidly growing bone in pediatrics.

Infection

Surfaces of IFF implants are generally designed to encourage soft and/or hard-tissue adherence, eventually leading to tissue integration. Unfortunately, this feature may also encourage bacterial adhesion. Soft-tissue infections and osteomyelitis are serious complications associated with implants, particularly with open fractures, external fixation devices, and intramedullary nailing. Consequences of implantassociated infections include prolonged hospitalization with systemic antibiotic therapy, several revision procedures, possible amputation, and even death. Serious complications are a great problem due to the emergence of antibiotic resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA). Hence modifying the actual metal implant surface to inhibit or reduce initial bacterial adhesion may be an option.

Our recent work has looked at visualization and quantification of Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus mutans, and Pseudomonas aeruginosa adhering to various surfaces including standard microrough cpTi and TAN surfaces, electropolished cpTi and TAN surfaces, and standard electropolished stainless steel. Significantly more live bacteria were observed on standard microrough TAN surfaces than on the other metal surfaces. There was no significant difference in the amount of bacteria found on the other surfaces. Such an observation suggests that the standard microrough TAN surfaces encouraged S aureus adhesion, and could lead to higher infection rates in vivo. Hence polishing TAN surfaces could be advantageous in osteosynthesis areas in minimizing bacterial adhesion and lowering the rate of infection. In the case of infection prevention chemistry and alternative technology with active biological surface modifications for prevention of bacterial adhesion and infection at the implant site will have a stronger future than pure topographical modification.

Fig 3

Modified universal humeral

nails used in our current study on nail removal. Left, polished test TAN nail with mirror like surface, middle, standard microrough surface TAN nail with matt surface, and right, polished standard surface steel nail with smooth surface.

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Fig 4

4-hole LCPs used with locking screws in our current cpTi

(silver), standard microrough cpTi (gold), polished anodized titanium (blue) and electropolished stainless steel control (silver).

We have developed topographies to answer clinical questions without having to worry about shelf life and other concerns with chemical/biological modifications. Topographical modifications can be robust, cheap, and permanent, whether in storage or in the body and (in the case of metals) can override other cues of information to the cell such as chemistry. This gives topographical surface modification a good solid platform to start from. On top of this, topographical surface modifications, unlike chemical modifications, should not need extra approval before clinical use. Polishing various implant surfaces has the potential to reduce the torque required for their removal, reduce soft tissue problems, and in the case of TAN, reduce bacterial attachment.

In situations with either hard or soft tissue interactions with biocompatible bulk materials, the ‘implant biocompatibility’ is determined more by the design and surface characteristics.

Without surface modification an implant may be biocompati-

Geoff, whose degree was in cell and immunobiology, completed a masters in electron microscopy and received a PhD in cell adhesion at The University of Wales, Aberystwyth. He has authored over 50 peer reviewed papers and more than 200 abstracts, has 1 patent and 2 are pending. He has supervised 6 PhDs, 13 masters, 3 medical theses, and 2 diplomas with several more ongoing. He is cofounder and Editor-in-Chief of the first and only online open access biomaterials journal: “Euro-

ble in one anatomical situation, yet not in another. Polishing is not the answer to everything, though may have use in certain clinical applications as mentioned within this article.

There is no ‘one surface’ for all applications and surfaces on one implant interacting with different tissues need to be considered as separate entities.

R Geoff Richards, Prof Dr Sci

Program Leader Bio-performance of Materials & Devices AO Research Institute, Davos, Switzerland geoff.richards@aofoundation.org

pean Cells & Materials” (www.ecmjournal.org) which has 4,850 registered readers worldwide and is indexed by Medline among others. Geoff is an honorary Senior Research Fellow at the University of Glasgow, honorary lecturer at Aberystwyth University and has a 3 year visiting Professorship at Tokyo Medical and Dental University, Japan. He is President of the Swiss Society for Biomaterials and has organised many conferences and symposiums within this field.

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cover theme polytrauma management

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Sebastian Lippross, Mauro Alini

Platelet-rich plasma for bone healing— to use or not to use?

Introduction

At the beginning of the 21st century, the clinical application of platelet-rich plasma (PRP) was considered a breakthrough in the stimulation and acceleration of bone and soft tissue healing. Since then, its use has been predominantly in maxillofacial surgery as an autologous additive to bone grafts and soft tissue transplants, although other indications such as chronic diabetic ulcers and some standard orthopedic procedures have been suggested. This article will clarify the rationale behind the clinical application of PRP by reviewing the literature and outlining some of our own observations in basic research.

Platelets and the growth factors they release are essential for regulating the cellular events that follow tissue damage. They adhere, aggregate, form a fibrin mesh, and subsequently release a large variety of growth factors and cytokines. At least 15 different factors are known to be contained within platelets [1–3], including platelet derived growth factor (PDRF-bb, -ab und -aa isoforms), transforming growth factor-beta (TGFbeta, -beta1 and -beta2 isoforms), platelet factor 4 (PF4), interleukin 1 (IL-1), platelet-derived angiogenesis factor (PDAF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), llatelet-derived endothelial growth factor (PDEGF), epithelial cell growth factor (ECGF), insulin-like growth factor (IGF), osteocalcin (Oc), osteonectin (On), fibrinogen (Fg), vitronectin (Vn), fibronectin (Fn) und thrombospontin-1 (TSP-1). The impact on bone and tissue regenera-

tion of most of these factors has been recognized by many authors [4–13]. As opposed to an artificial composition of recombinant proteins, PRP maintains the natural concentrations within a cocktail of growth factors acting on multiple pathways [14]. Furthermore, artificial recombinant growth factors require further synthetic or animal proteins as carriers. PRP in contrast serves as a natural carrier itself [15].

Thereby PRP can mimic the highly efficient in vivo situation much more closely than a custom designed protein preparation.

As platelet concentrates can be prepared from whole blood within a short time using relatively simple methods, they have the potential to be an immunogenically inert additive to promote rapid healing and tissue regeneration. Preparation of platelet concentrates usually requires a two step centrifugation procedure [16]. In the first step full blood is divided into a platelet-containing and a cell-containing fraction [17]. During the second step, which is high speed centrifugation, platelets can be sedimented and rediluted to the desired volume of plasma (usually 1/10 of the initial blood volume) yielding platelet concentrations of more than 1,000,000 platelets/μl [15, 17]. To release the growth factors and cytokines, platelets need to be activated. In vivo this happens through platelet agonists like thrombin, collagen, ADP, serotonin, and thromboxane A2. For experimental purposes, bovine thrombin and CaCl2 are the most commonly used agents. In our own studies

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we have demonstrated equal efficacy for freeze-thaw-activation of PRP [18]. In clinical practice PRP is used as a liquid, made from 50–100ml of full blood that quickly forms a gel when applied with thrombin. Several companies have developed kits and devices for automatic preparation during surgical procedures.

Although the general concept seems plausible, controversy remains about whether PRP and other platelet preparations meet the high expectations set by the clinical demands. For the practitioner it appears very difficult to obtain information on the actions and the possible risks of using platelet concentrates.

Clinical safety considerations

Clearly an autologous preparation does not bear the risks of transmissible diseases nor of immunogenic reactions. If commercially available devices are used, FDA approval will usually ensure that the preparation

Table 1

process is carried out in a sterile and pyrogen free manner. We are not currently aware of any serious adverse effects that have occurred when PRP was used for wound healing and bone grafting. Still, a possible risk arises from bovine thrombin that is used to activate PRP. Coagulopathies due to antibody formation against thrombin, Factor V, and Factor XI have been reported after cardiac surgery [19, 20].

Basic research—in vitro and in vivo effects of autologous platelet concentrates While there are numerous case stud-

ies and small clinical trials on the clinical applications, knowledge about the underlying effects at the cellular level is limited. Nevertheless, PRP has been shown to stimulate cell proliferation of osteoblasts and fibroblasts and to upregulate osteocalcin in these cells [21, 22]. In a recent study by our own group we demonstrated the differentiation of mesenchymal stem cells (MSC) into bone forming cells in the presence

Application in bone healing

Application

Type of study

Study design

Conclusion

Reference

Treatment of intra-

Comparative

70 interproximal intrabony osseous

Treatment with PRP and HA led to

[32]

bony defects

controlled clini-

defects were treated with PRP and a

significantly more clinical im-

cal study

ceramic porous hydroxyapatite (HA)

provement than HA and saline

scaffold or HA and saline Treatment of intra-

Randomized

Bilateral periodontal intrabony de-

PRP significantly increased the

bony defects

clinical trial

fects were matched in 13 individuals

clinical periodontal response of le-

(split mouth,

and treated only with a bovine xeno-

sions treated with xenogenic bone

double masked)

graft or with PRP

grafts

Treatment of

Prospective case

Five similar bilateral paired infrabony

Similar gain in clinical attachment

infrabony defects

series

defects were treated with autologous

level and probing depths in APC

platelet concentrate (APC) or a biore-

and MEM treated groups

[33]

[34]

sorbable barrier membrane (MEM) Lumbar spine fusion

Prospective re-

23 individuals underwent transforam-

2-year minimum follow-up

view compared

inal lumbar interbody spinal fusion

showed faster healing in the PRP

to historical

(TLIF) with PRP compared to histori-

group, but no significant differ-

results

cal results

ence in the pseudarthrosis rate

[35]

was observed Total ankle replace-

Comparative

114 and 66 Agility total ankle replace-

Autologous concentrated growth

ment

Study

ments were performed without and

factors appeared to make a sig-

with autologous concentrated growth

nificant positive difference in the

factors for distal syndesmosis fusion

syndesmosis union rate in total

[36]

ankle replacements Treatment of mandib- Prospective

44 individuals were treated with bone

Maturity index of bone grafts

ular continuity de-

graft and PRP and bone graft alone

with PRP was higher than in bone

fects in tumor cases

study

grafts alone

[37]

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of PRP [18]. An increase in growth and differentiation of PRPtreated periodontal ligament cells has been shown by two groups [10, 23]. Further investigation revealed stimulation of the mitogenic (ie, transforming) response to PRP in human trabecular and rat bone marrow cells [24, 25]. Additionally, we were able to demonstrate a strong effect on the expansion of endothelial progenitor cells by platelet-released growth factors [26].

In vivo studies do not support the positive actions of PRP. In fact, in one of the most recent investigations PRP decreased the osteoinductivity of demineralized bone matrix in nude mice [27]. Other researchers performed trials on various animals and reported no beneficial effect of using PRP for bone healing [28] or suggest a low regenerative potential for its use in combination with xenogenic bone grafts [29]. Some studies also show effective augmentation of porous biomaterial in rats [30] and sheep [31]. Careful analysis of these studies reveals

Table 2

27

cover theme polytrauma management

that none are scientifically comparable. Therefore, we cannot draw an overall scientific conclusion of PRP actions in animal models.

Clinical trials and case studies Case reports and small clinical trials have been reported in craniomaxillofacial surgery as in other specialties. Table 1 and table 2 display a selection of such studies which overall support the beneficial effect of PRP and other platelet concentrates. As previously mentioned, in animal studies the two main factors making it almost impossible to compare any two of the studies published are the lack of a standardized PRP preparation protocol (Table 3) and the lack of commonly accepted evaluation criteria.

Other applications

Application

Type of study

Study design

Conclusion

Reference

Treatment of chronic

Cohort study

Out of a cohort of 150 patients with

Pain was reduced in patients

[38]

chronic elbow tendinosis, 15 were

treated with PRP compared to the

given one injection of PRP, and 5

control group in this pilot study

ellbow tendinosis

were given one injection of bupivacaine Treatment of diabetic

Prospective

40 individuals were randomized into

Significantly more ulcers healed in

foot ulcers

randomized

a PRP- and saline-gel group and fol-

the PRP group

controlled trial

lowed up for 12 weeks

Meta-analysis

More than 25,000 cases of diabetic

Ulcers treated with platelet con-

foot ulcers were treated with and

centrate were significantly more

without platelets

likely to heal

Treatment of diabetic foot ulcers

Table 3

[39]

[40]

Commercially available preparation systems

Device

Preparation time

Platelet yield (whole blood) as stated

Company

by manufacturer GPS

12 min

Up to 8

Cell Factor Technologies

20 min

Up to 7

Implant Innovations

Symphony II

15 min

Up to 6

DePuy

SmartPReP

15 min

Up to 9

Harvest Technologies Corp

Magellan

15 min

Up to 10

Medtronic

(gravitational platelet separation) PCCS (platelet concentrate collection system)

28

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Summary and conclusions PRP preparation provides a fairly simple method to deliver a variety of natural growth factors to the patient. High concentrations of proteins acting in concert through different pathways can be achieved by commercially available systems that can be used in the operating room. The risks of contamination and immunogenic response are considerably low when using FDA approved systems. The remaining risk of coagulopathies could be minimized by using alternative activation methods to standard bovine thrombin. On the whole, the beneficial effects of PRP in clinical application remain doubtful. No appropriate clinical investigations that meet all modern quality criteria have been conducted up to now.

Based on our own and other groups’ in vitro findings, one could hypothesize that PRP can be supportive of the healing processes if used in the right manner. The appropriate use of PRP has yet to be determined by larger randomized controlled trials. Additional basic investigations on the mechanisms of action could elucidate under which conditions PRP can act as a tissue healing additive.

Sebastian Lippross, MD

Biomaterials and Tissue Engineering Program AO Research Institute, Davos sebastian.lippross@aofoundation.org

Mauro Alini, PhD

Head of Biomaterials and Tissue Engineering Program AO Research Institute, Davos mauro.alini@aofoundation.org

Bibliography 1 Eppley BL, Woodell JE, Higgins J (2004) Platelet quantification and growth factor analysis from platelet-rich plasma: implications for wound healing. Plast Reconstr Surg; 114: 1502–1508.

2 Weibrich G, Kleis WK, Hafner G, et al (2002) Growth factor levels in platelet-rich plasma and correlations with donor age, sex, and platelet count. J Craniomaxillofac Surg; 30:97–102.

3 Yazawa M, Ogata H, Nakajima T, et al (2003) Basic studies on the clinical applications of platelet-rich plasma. Cell Transplant; 12:509– 518.

4 Bostrom MP, Saleh KJ, Einhorn TA (1999) Osteoinductive growth factors in preclinical fracture and long bone defects models. Orthop Clin North Am; 30:647–658.

5 Boyan BD, Ranly DM, Schwartz Z (2006) Use of growth factors to modify osteoinductivity of demineralized bone allografts: lessons for tissue engineering of bone. Dent Clin North Am; 50:217–28, viii.

6 Einhorn TA (1995) Enhancement of fracture-healing. J Bone Joint Surg Am; 77:940–956.

7 Glowacki J (1998) Angiogenesis in fracture repair. Clin Orthop Relat Res; S82–S89.

8 Laurencin CT, Ambrosio AM, Borden MD, et al (1999) Tissue engineering: orthopedic applications. Annu Rev Biomed Eng; 1:19–46.

9 Logeart-Avramoglou D, Anagnostou F, Bizios R, et al (2005) Engineering bone: challenges and obstacles. J Cell Mol Med; 9:72–84.

10 Lucarelli E, Beccheroni A, Donati D, et al (2003) Platelet-derived growth factors enhance proliferation of human stromal stem cells.

Biomaterials; 24:3095–3100.

11 Mistry AS, Mikos AG (2005) Tissue engineering strategies for bone regeneration. Adv Biochem Eng Biotechnol; 94:1–22.

12 Salgado AJ, Coutinho OP, Reis RL (2004) Bone tissue engineering: state of the art and future trends. Macromol Biosci; 4:743–765.

13 Street J, Bao M, deGuzman L, et al (2002) Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover. Proc Natl Acad Sci USA; 99:9656–9661.

14 Anitua E, Andia I, Ardanza B, et al (2004) Autologous platelets as a source of proteins for healing and tissue regeneration. Thromb Haemost; 91:4–15.

15 Marx RE (2001) Platelet-rich plasma (PRP): what is PRP and what is not PRP? Implant Dent; 10:225–228.

16 Weibrich G, Kleis WK, Kunz-Kostomanolakis M, et al (2001) Correlation of platelet concentration in platelet-rich plasma to the extraction method, age, sex, and platelet count of the donor. Int J Oral Maxillofac Implants; 16:693–699.

17 Barthelmai W (1969) [Isolation of thrombocytes from small blood volumes]. Klin Wochenschr; 47:266–270.

18 Meury T KLSTAM. Effect of platelet-rich-plasma on bone marrow stromal cell differentiation. [abstract]. ASBMR 26th annual meeting.

2007.

19 Cmolik BL, Spero JA, Magovern GJ, et al (1993) Redo cardiac surgery: late bleeding complications from topical thrombin-induced factor V deficiency. J Thorac Cardiovasc Surg; 105:222–227.

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20 Spero JA (1993) Bovine thrombin-induced inhibitor of factor V and bleeding risk in postoperative neurosurgical patients. Report of three cases. J Neurosurg; 78:817–820.

21 Graziani F, Ivanovski S, Cei S, et al (2006) The in vitro effect of different PRP concentrations on osteoblasts and fibroblasts. Clin Oral Implants Res; 17:212–219.

22 Dolder JV, Mooren R, Vloon AP, et al (2006) Platelet-Rich Plasma: Quantification of Growth Factor Levels and the Effect on Growth and Differentiation of Rat Bone Marrow Cells. Tissue Eng. 23 Annunziata M, Oliva A, Buonaiuto C, et al (2005) In vitro celltype specific biological response of human periodontally related cells to platelet-rich plasma. J Periodontal Res; 40:489–495.

24 Gruber R, Varga F, Fischer MB, et al (2002) Platelets stimulate proliferation of bone cells: involvement of platelet-derived growth factor, microparticles and membranes. Clin Oral Implants Res; 13:529– 535.

25 Oprea WE, Karp JM, Hosseini MM, et al (2003) Effect of platelet releasate on bone cell migration and recruitment in vitro. J Craniofac Surg; 14:292–300.

26 Lippross S, Verrier S, Hoffmann A, et al (2007) Platelet released growth factors boost expansion of endothelial progenitor cells [abstract]. 53rd Annual Meeting of the Orthopaedic Research Society 2007; Poster No 481.

27 Ranly DM, Lohmann CH, Andreacchio D, et al (2007) Plateletrich plasma inhibits demineralized bone matrix-induced bone formation in nude mice. J Bone Joint Surg Am; 89:139–147.

28 Pryor ME, Yang J, Polimeni G, et al (2005) Analysis of rat calvaria defects implanted with a platelet-rich plasma preparation: radiographic observations. J Periodontol; 76:1287–1292.

29 Sanchez AR, Sheridan PJ, Eckert SE, et al (2005) Regenerative potential of platelet-rich plasma added to xenogenic bone grafts in peri-implant defects: a histomorphometric analysis in dogs. J Periodontol; 76:1637–1644.

30 Rai B, Oest ME, Dupont KM, et al (2007) Combination of plateletrich plasma with polycaprolactone-tricalcium phosphate scaffolds for segmental bone defect repair. J Biomed Mater Res A. 31 Lucarelli E, Fini M, Beccheroni A, et al (2005) Stromal stem cells and platelet-rich plasma improve bone allograft integration. Clin Orthop Relat Res; 62–68.

32 Okuda K, Tai H, Tanabe K, et al (2005) Platelet-rich plasma combined with a porous hydroxyapatite graft for the treatment of intrabony periodontal defects in humans: a comparative controlled clinical study. J Periodontol; 76:890–898.

33 Hanna R, Trejo PM, Weltman RL (2004) Treatment of intrabony defects with bovine-derived xenograft alone and in combination with platelet-rich plasma: a randomized clinical trial. J Periodontol; 75:1668–1677.

34 Papli R, Chen S (2007) Surgical treatment of infrabony defects with autologous platelet concentrate or bioabsorbable barrier membrane: a prospective case series. J Periodontol; 78:185–193.

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35 Hee HT, Majd ME, Holt RT, et al (2003) Do autologous growth factors enhance transforaminal lumbar interbody fusion? Eur Spine J; 12:400–407.

36 Coetzee JC, Pomeroy GC, Watts JD, et al (2005) The use of autologous concentrated growth factors to promote syndesmosis fusion in the Agility total ankle replacement. A preliminary study.

Foot Ankle Int; 26:840–846.

37 Marx RE, Carlson ER, Eichstaedt RM, et al (1998) Platelet-rich plasma: Growth factor enhancement for bone grafts. Oral Surg Oral Med Oral Pathol Oral Radiol Endod; 85:638–646.

38 Mishra A, Pavelko T (2006) Treatment of chronic elbow tendinosis with buffered platelet-rich plasma. Am J Sports Med; 34:1774–1778.

39 Driver VR, Hanft J, Fylling CP, et al (2006) Autologel Diabetic Foot Ulcer Study Group. A prospective, randomized, controlled trial of autologous platelet-rich plasma gel for the treatment of diabetic foot ulcers. Ostomy Wound Manage; 52:68–70, 72, 74.

40 Margolis DJ, Kantor J, Santanna J, et al (2001) Effectiveness of platelet releasate for the treatment of diabetic neuropathic foot ulcers.

Diabetes Care; 24:483–488.

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David W Grainger

Biotechnology in musculoskeletal surgery: outlook and expectations

Biotechnology represents a complex and diverse technical field involving the fusion of modern biological methods that innovate new products, capabilities and enabling technologies to improve the quality of human life. Much argument abounds in the literature on a single definition: each precise meaning depends on field of use and context. In present economic terms, biotechnology equates to drug innovation where modern pharmaceutical pipelines are stocked with drug candidates produced from biotechnology methods. But those same technologies are driving many other biomedical opportunities, some relevant to musculoskeletal repair. A previous AO Dialogue article [1] and recent AO series book chapter [2] introduced some general features of biotechnology use in medicine.

Most biotechnology strategies applicable to medicine are focused on new drug products from biotechnologies (eg, therapeutic peptides, proteins, and transgenes), incorporation of these bioactive agents into delivery systems (carriers, coatings, matrices), products of biotechnology (recombinant fibrin glues, collagens, viral vectors, bio-engineered polysaccharides), use of altered living cells as producers of therapeutic agents or functional tissue replacements either in vitro (bioreactors) or in vivo (cell therapy, regenerative medicine). Further, active cells, therapeutic bio-derived compounds and biomaterials are combined implant biomaterials (tissue engineered constructs as cartilage and bone substitutes), and hybrid cell/ protein and chemical reporting constructs are exploited as advanced imaging tools (molecular beacons, genetically altered cell probes, targeted molecular imaging agents). As capabilities and creativity are unbridled, medicinal possibilities and surgi-

cal applications for these materials will only expand [3]. Methods in tissue engineering use many forms of biotechnology— combining growth factors or other cell signaling molecules, biomaterials scaffolds to provide form and support, seeded viable cell populations to enable tissue regeneration, and appropriate bioreactors that promote recapitulation of viable tissue form and function for novel implantable constructs. The approach is rapidly merging with regenerative medicine, often used synonymously to signify the unified goal and strategy for reproducing lost tissue or physiological functions with therapeutic and clinical potential. Bone and cartilage are primary foci for biotechnology research, attempting to improve functional tissue healing and neogenesis with varying degrees of clinical success and failure.

From an academic perspective, biotechnology represents a “blue sky” field: rapid advances have been made since the 1985 Nobel Prize was awarded for the polymerase chain reaction and “recombinant” became routinely used in the Wall Street Journal. The 21st century has been coined the “Century for Biology” reflecting expectations of what diverse biotechnology contributions might promise for therapeutic breakthroughs.

Nonetheless, the gap between preclinical research and clinical applications is substantial. Many current biotechnology studies provide ambivalent or starkly contrasting musculoskeletal outcomes. The lack of mechanistic details in many ‘cocktail’ approaches to treating difficult trauma situations with mixtures of cells, genes, proteins, and biomaterials reflects the quite typical development of a complex field seeking

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Table 1

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cover theme polytrauma management

Anticipated biotechnology impacts on research, preclinical and clinical components of musculoskeletal repair.

Biotechnology target

Expectations

Improved in vivo models for preclinical evaluations

Genetically altered small and large experimental animal models that more accurately reproduce aspects of human physiology, disease, and healing

New bioreactor-based ex vivo/in vitro living Reduced cost, more accessible living and non-living biomimetic models for testing tissue equivalents and tissue phantoms therapeutic manipulations of tissue and avoid animal use Advanced patient diagnostics and rapid genetic analysis

Rapid, molecular level diagnosis and biomarker profiling of bone and connective tissue disease states and risks, prediction of optimal drug therapies (pharmacogenomics) and outcomes

Treatment of osteoporosis and fragility fractures

Advanced molecular imaging tools, improved diagnostic and screening reagents and methods, new interventional therapies from innovative biopharmaceutical drugs and new devices, improved patient identification and prophylaxis

Improved cell and molecular biology tools, methods and probes to advance musculoskeletal research

Improved understanding of the biological basis of healing, identification of markers of

Solutions to large bone defects, nonunions, enhanced bone healing

Therapeutic gene and bioengineered growth factor delivery, tissue-engineered bone

disease, genetically programmed cell types for therapies, exploitation of pluripotent cells to program wound healing and bone neogenesis, cells as advanced imaging tools

regeneration, cell-based healing, reliable therapeutic vasculogenesis and new smallmolecule bone regenerative drugs Elucidation of pathogenesis mechanisms associated with implant-centered infection,

Mitigating infection

new anti-microbials addressing virulence and resistance mechanisms, new methods to better deliver antimicrobials to implant sites, novel combination device and biomaterials-based approaches to limit device and wound-site colonization Depends upon regulatory and reimbursement strategies that provide economic

Reduce health care costs

incentives, drive competition, and increase treatment options

simple solutions without many driving hypotheses. A confounding, dizzying array of biotech opportunities exist for new approaches to trauma treatments, but many without substantial scientific validation to date. However, research progress must move from the current ‘black box’ and ‘blue sky’ endeavors to actually place significant tools in the hands of clinicians. Table 1 highlights many possible areas where impacting contributions are expected from preclinical to clinical use. Several prospects and prognostications are reviewed briefly below in some relevant areas.

1 Osteoporosis and fragility fractures. Anticipated biotechnology contributions: advanced imaging, new interventional therapies, prophylaxis.

Imaging New noninvasive imaging tools rely on new reagents with target-specific sensitivity and fidelity to provide molecular and cellular level details. Molecular targeting and

imaging reagents are now combined with new optoelectronic tools to improve lesion and tissue-specific contrast. Research animals that express fluorescent proteins (GFP) in their cells either constitutively, locally, or upon introduction of an exogenous cue are widely available. Hybrid molecular probes containing both tissue specific agents and contrast agents that provide disease-specific activation via site-specific enzymatic cleavage or targeting unfolding reactions have been developed.

Fiber-optic based tissue imaging is desirable using far red and near-infrared (IR) light that travels through tissues most efficiently and thus often used for whole animal imaging. However, IR-active tissue probes for such systems are rare. Now, protease-activatable IR-active imaging probes can reveal in vivo cathepsin B enzyme activity specific to tumor sites and this strategy should be extended to musculoskeletal tissue enzymes as well. Harvested autologous bone marrow cells can also be retrovirally transduced to constitutively express flourescent/luminescent fusion proteins and reintroduced to the rat. Over 4 weeks posttransplantation, the whole body distribution of transduced rat cells has been monitored using

32

noninvasive bioluminescence imaging. Further novel molecular and cellular homing agents, combinations with nanophased contrast agents (eg, particles) and associated instrument innovation will continue to improve both resolution and site-specificity in bone, cartilage, and connective tissue.

New drug targets Molecular and cellular studies reveal that osteoblasts produce a protein signaling molecule—macrophage colony-stimulating factor—that induces macrophage proliferation. A second osteoblast protein, RANKL, also binds to a different macrophage receptor, inducing differentiation into osteoclasts. A third osteoblast protein—osteoprotegerin—blocks osteoclast formation by binding RANKL and blocking its receptor interaction on macrophages. Parenteral delivery of recombinant osteoprotegerin, a fragment of the TNF receptor family protein (also called OCIF), to limit osteoclast formation, is a new therapeutic approach, reducing rates of bone resorption by at least 60% in humans. Other molecular blockades against RANKL, such as recombinant antibodies, are being developed with this capacity. Several other known molecules in signaling pathways controlling bone formation and resorption—including estrogen, parathyroid hormone (PTH), and insulin-like growth factor-1 (IGF-1)—have biotechnology development histories. Estrogen’s known nuclear transcriptional DNA regulation is also accompanied by distinct osteoblast kinase-coupled receptor binding in bone that prompts increased osteoprotegerin and reduced RANKL production, suppressing osteoclast formation. Estrogen extends osteoblast survival while simultaneously inducing osteoclast death. Reduced estrogen levels accompanying menopause decrease this inhibition of osteoclast formation and resorptive activity, as well as bone building activity. PTH behaves in the opposite way by regulating RANKL and osteoprotegerin to trigger osteoclast formation indirectly by binding to osteoblasts and prompting them to increase RANKL and decrease osteoprotegerin production, respectively. Despite this resorptive action, the recombinant PTH fragment (Forteo™, approved 2002, Eli Lilly) represents the first efficacious bone-building drug. Endogneous PTH at continuously elevated levels over long periods promotes bone resorption; periodic intermittent PTH injections build bone (known since 1928 from bone density studies in dogs but ignored for 50 years) by promoting osteoblast maturation and lengthening osteoblast lifespan, enhancing numbers of bone-forming osteoblasts that function longer. In both men and postmenopausal women, intermittently administered PTH increases bone density (notably in spine), enhances bone structural integrity, and prevents fractures. Daily PTH injections increase bone density 8–10% after one year, reducing fracture risk by 60%.

Wide differences in human serum IGF-1 levels, genetically programmed but related in part to PTH levels, have important

AODIALOGUE 1 | 07

implications for bone density and fracture incidence. IGF-I normally circulates as a complex with the BP3 binding protein; appreciable free IGF-I is not normally found in blood and is rapidly cleared from circulation. Administration of free IGF-I at potentially therapeutic doses exerts acute insulin-like side effects and lower doses exhibit limited, transient efficacy.

Somatokine™ (Insmed) is the biotechnology-derived recombinant equivalent of IGF-1 complexed with BP-3 in a single molecule, studied for bone mass enhancement. Other, improved biopharmaceuticals will likely result from biotechnological discoveries regarding osteoporosis at the genetic, molecular and cellular levels, providing new therapeutic targets.

2 Bone defects, nonunions, enhanced bone healing. Anticipated biotechnology contributions: gene-based and engineered growth factor delivery, tissue engineered bone regeneration, cell-based healing, therapeutic vasculogenesis, and bone regenerative therapies.

Biopharmaceutical therapies

Similar to osteoporosis, new biotechnologically derived drugs are sought to augment natural healing, accelerate bone formation and produce clinically relevant amounts of new bone in areas of damaged or diseased skeletal tissue. Many more protein-based drugs for bone neogenesis, primarily recombinant growth factors (eg, cytokines and chemokines), have been reported than can be mentioned here. Notably, the TGF-b superfamily of bone morphogenetic proteins (BMPs) is the most studied and the most lucrative clinical products to date. Recombinant human BMP-2 (rhBMP2, as InFuse™, Medtronics) enjoys a substantial investigative base and clinical use, mostly off-label. Many BMPs have shown comprehensive bone inductive properties when delivered locally either as the pure recombinant protein, or as a transgene plasmid [4, 5]. Efficacy varies based on animal model, patient age and health, wound site biology, and dosing.

Platelet derived growth factor (PDGF-BB) has produced promising results in several bone healing scenarios and appears promising as another bone-targeted cytokine therapy. Two primary limitations are evident in these cytokine delivery strategies: (1) that a single growth factor is necessary but possibly not 100% sufficient to fully, reliably recapitulate rapid bone regrowth, and (2) that direct delivery of the protein agent to the wound site can often be dose and activity limiting, with site-dependent efficacy. Multiple growth factor delivery is intuitive since this is precisely how cell-mediated healing functions in vivo. However, multiple agent delivery to bone sites lacks design parameters: sequential timing and dosing of these endogenous agents in bone healing sites in vivo is unknown and therefore rational duplication is impossible.

Nonetheless, several combination growth factor therapies have been reported for bone formation [6, 7]. Delivery of the

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therapeutic transgene for each cytokine (eg, BMP2, VEGF, or PDGF) avoids limitations of direct protein drug delivery [8, 9].

However, control features on therapeutic gene expression (on/ off), duration, and dosing are currently problematic for reliable routine use. Delivery of multiple transgenes might better duplicate endogenous BMP and cytokine synergies in vivo [10]. Additionally, viral vectors, while extremely efficient for transgene delivery to cells, are accompanied by serious risks of immune reactions. Naked plasmids and nonviral gene delivery vectors are being studied as alternative gene delivery strategies to bone, some with creative wound-healing responsive designs [11], but are plagued generally by poor delivery efficiencies in vivo and cell toxicity in some cases [12]. Future biotechnology improvements are critical: new innovative viral vector modifications to reduce local dose requirements and host response, more effective nonviral vectors for local gene delivery, and bioengineered cells (eg, ex vivo modified stem cells) with introduced therapeutic cytokine genes targeted to injury sites upon injection. New drug conjugates, recombinant protein signal molecules, and small molecule surrogates with therapeutic mitogenic or morphogenic properties in musculoskeletal repair are inevitable.

33

Cell-based approaches Many osteo-inductive biomaterials have been described but their almost uniform disappointing clinical performance to date is notable. Most notable recent innovation in this area involves biomaterials scaffolds enhanced with biotechnology: tissue-engineered implantable constructs capable of reproducing tissue form and function using viable cells and potent drug combinations [13, 14]. To improve in vivo performance, integrated understanding of intrinsic biological factors and kinetics governing bone and tissue development in vivo, and their appropriate therapeutic exploitation and functional control in situ are essential. Tissue engineering methods are now inseparable from modern pharmaceutics in using materials science, cellular and molecular biology to identify therapeutic targets, produce bioactive substances and deliver them specifically to tissue sites to promote specific biological responses. Most therapeutically important neotissues will require production of transportcompetent organized vascular and neural networks for survival. Defect neovasculogenesis remains an unsolved problem: nothing regenerates without adequate perfusion. This is limiting production of three-dimensional implants without cell necrosis and viability issues. Numbers of requisite endo-

34

AODIALOGUE 1 | 07

thelial progenitor cells vary enormously across species making cross-comparisons difficult. The capability of angiopotent cell types to adequately and rapidly restore perfusion to defect sites to enable normal healing remains to be seen. Intraoperative solutions to this problem are difficult. Biotechnological enhancements of conventional scaffold approaches to bone induction and regeneration require further work to distinguish themselves as reliable alternatives. It appears that simply mixing all biological components or primordial tissue into a porous biomaterial and implanting it into a wound site is insufficient in most cases to produce the desired clinical endpoint. That is, being present is not functionally equivalent to timing and dosing of endogenous presentation.

Progenitor cell-based strategies represent an area of current excitement and promise. Stem cell therapies are certainly politically and scientifically dominant, but mesenchymal stem cells in particular, with their capacity to differentiate to osteoblast, chondrocyte, fibroblast, and adipocyte cells, have attracted substantial orthopedic and trauma attention [15, 16].

MSCs vary in their regenerative capacity, but have been used successfully in human bone repair [17]. Identification of factors and pathways that promote reliable MSC osteogenic commitment and allow use of MSCs with functional potential for optimal bone repair remains a critical challenge. Age and source-related regenerative variability are also important issues. Bone-healing acceleration in response to osteogenic factors appears to result from increased recruitment in responsive MSCs from the soft-tissue compartment around the bone site, specifically sourced from muscle, fascia, vasculature, and nerves (ie, cell recruitment and differentiation). Lastly, the distinct roles of local biomechanical stimuli versus the intrinsic MSC mitogenic and morphogenic potential of the bone healing site remain to be distinguished and exploited in musculoskeletal healing scenarios. MSC coordination of vasculogenesis could be mechanically cued [18]. In these contexts, further MSC genomic and proteomic analyses should help identify molecules and mechanisms that promote reliable, sustained osteogenic MSC mitogenic and morphogenic potential.

3 Infection. Anticipated biotechnology contributions: elucidation of pathogenesis mechanisms associated with implant-centered infection, new antimicrobials, new methods to deliver antimicrobials to implant sites, novel combination device and biomaterials-based approaches to limit device colonization.

Infection risk in an antibiotic-resistant era is a continuing concern, and increasing implant incidence increases that risk of infection [19, 20]. Modern pathology and infectious disease research has been aided immensely by biotechnology meth-

ods. Model pathogen knock-outs, recombinant assay reagents, and microbial genetic profiling provide enormous amounts of new information about infection and disease, antibiotic resistance mechanisms, and potential new antimicrobial targets.

This is now applied to device-centered infection problems and elucidation of new antibiotics. Traditional synthesis of natural antibiotics is often tedious, sometimes impossible or uneconomical. Biotechnology methods permit fermentation of genetically engineered microbial cultures to mass-produce complex natural products and drug libraries beyond current reach of organic chemists. Additionally, new antimicrobial biomaterials strategies to limit adherence and colonization, inactivate pathogenic phenotypes (eg, by confounding microbial quorum sensing), and locally deliver new antimicrobials more effectively will emerge from biotechnology contributions to this area. Infection prevention is much more effective than post facto attempts to eliminate it, so that prophylaxis is more attractive in new antiinfectives.

Other considerations for biotechnology

Two further issues cloud the horizon for clinical adoption of biotechnology: insurance reimbursement and regulatory strategies. Regardless of research promise or clinical efficacy, these two hurdles represent rate-limiting steps to introducing experimental technology to the population at large. Reimbursement policies determine to a large extent whether any medical innovation is readily adopted by clinicians, and, importantly, whether biotechnology firms (and their stockholders) can risk investment into product development and innovation [21]. Regulatory policies differ widely in biotechnology across countries and continents [22]. Transparent, uniform processes are currently lacking. The United States in particular faces a landmark decision in 2007 about regulating so-called bio-generics—pharmaceuticals of biotechnology origin coming off patent. This policy will dictate to a large extent financial requirements for bringing new biotechnology products through the approval path to market, and how future products will be developed and innovated with this model, and in what specific clinical areas [23]. Cell therapy products in particular remain an outstanding example of research intrigue and promise, and regulatory doubt: such therapies might not offer product designs for wide clinical adoption that can pass through regulatory requirements with sufficient market economics to provide incentive for their development [24, 25].

Acknowledgements: The author thanks the many colleagues who have imparted valuable perspectives, wisdom, and insight. The field is far too big to go at it alone.

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cover theme polytrauma management

David W Grainger, PhD

Member, AO AcC, BAB Inaugural George S & Dolores Doré Eccles Presidential Endowed Chair of Pharmaceutics and Pharmaceutical Chemistry, and Professor of Bioengineering Departments of Pharmaceutics and Pharmaceutical Chemistry, and Bioengineering University of Utah, Salt Lake City, USA david.grainger@utah.edu

Bibliography 1 Grainger DW (2006) Update on AO-sponsored research in biotechnology. AO Dialogue; 1:34–37.

2 von Rechenberg B, Meinel L, Grainger DW, et al (2006) Introduction to biotechnology. Rüedi TP, Buckley RE, Moran CG (eds) AO Principles of Fracture Management. 2nd ed. Stuttgart New York: Thieme Verlag.

3 Gurtner GC, Callaghan MJ, Longaker MT (2007) Progress and potential for regenerative medicine. Ann Rev Med; 58:299–312.

4 Einhorn TA (2003) Clinical applications of recombinant human BMPs: early experience and future development. J Bone Joint Surg Am; 85(90003):82–88.

5 Seeherman H, Wozney JM (2005) Delivery of bone morphogenetic proteins for orthopedic tissue regeneration. Cytokine Growth Factor Rev; 16(3):329–345.

6 Chen RR, Mooney DJ (2003) Polymeric growth factor delivery strategies for tissue engineering. Pharm Res; 20:1103–1112.

7 Puleo DA (2003) Biotherapeutics in orthopedic medicine. Drug Develop; 17:301–314.

8 Jang J-H, Houchin TL, Shea LD (2004) Gene delivery from polymer scaffolds for tissue engineering. Exp Rev Med Dev; 1:127–138.

9 Musgrave DS, Bosch P, Ghivizzani S, et al (1999) Adenovirusmediated direct gene therapy with bone morphogenetic protein-2 produces bone. Bone; 24(6):541–547.

10 Franceschi RT, Yang S, Rutherford RB, et al (2004) Gene therapy approaches for bone regeneration. Cells Tissues Organs; 176:95–108.

11 Schmoekel HG, Weber FE, Schense JC, et al (2005) Bone repair with a form of BMP-2 engineered for incorporation into fibrin cell ingrowth matrices. Biotechnol Bioeng; 89:253–262.

12 Partridge KA, Oreffo RO (2004) Gene delivery in bone tissue engineering; progress and prospects using viral and non-viral strategies. Tissue Engineering; 10:295–307.

13 Davies JE (2001) Bone Engineering. EM Squared, Inc.: Toronto.

14 Mistry AS, Mikos AG (2005) Tissue engineering strategies for bone regeneration. Regenerative Medicine II, Yannas IV (ed), Adv Biochem Eng Biotechnol series; 94:1–22.

15 Caplan AI (2005) Mesenchymal stem cells: cell-based reconstructive therapy in orthopedics. Tissue Engineering; 11(7–8):1198–1211.

16 Rahaman MN, Mao JJ (2005) Stem cell-based composite tissue constructs for regenerative medicine. Biotechnol Bioeng; 91(3):261–284.

17 Quarto R, Mastrogiacomo M, Cancedda R, et al (2001) Repair of large bone defects with the use of autologous bone marrow stromal cells. NEJM; 344:385–386.

18 Kasper G, Dankert N, Tuischer J, et al (2007) Mesenchymal stem cells regulate angiogenesis according to their mechanical environment. Stem Cells; 25:903–910.

19 Darouiche RO (2004) Treatment of infections associated with surgical implants. N Engl J Med; 350(14):1422−1429.

20 Harris LG, Richards RG (2006) Staphylococci and implant surfaces: a review. Injury; 37(Suppl 2):S3–14.

21 Phillips KA (2006) The intersection of biotechnology and pharmacogenomics: health policy implications. Health Affairs; 25:1271–1280.

22. Patterson LA (1999) A Comparison of biotechnology regulatory policy in the United States and the European Union. In the European Union Studies Association (EUSA) Biennial Conference 1999 (6th); Pittsburgh, PA, USA. 23 Swanson RA (1986) Entrepreneurship and innovation: biotechnology. In The Positive Sum Strategy: Harnessing Technology for Economic Growth; National Academy Press, Washington, DC, USA. 24 Daniels JT, Secker GA, Shortt AJ et al (2006) Stem cell therapy delivery: treading the regulatory tightrope. Regen Med; 1:715–719.

25 Halme DG, Kessler DA (2006) Regulation of stem-cell–based therapies. New Engl J Med; 355:1730–1735.

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Martin Bircher

Pelvic and acetabular fractures Past, present, and future

Introduction This article is a written summary of the Marvin Tile 2006 Lecture given by Martin Bircher. The Marvin Tile Lecture is given at the University of Toronto Pelvic and Acetabular Fracture course to recognize Marvin Tile for his outstanding contributions to orthopedic surgical teaching and in particular his commitments to pelvic and acetabular fracture treatment. In 1987, Mr Bircher was a Marvin Tile fellow when his passion for trauma management and treatment of pelvic and acetabular injuries was ignited. Mr Bircher returned to London, England, where he put his passion into action, becoming one of the most respected pelvic and acetabular fracture surgeons in the United Kingdom. This paper entitled “Pelvic and acetabular fractures—past, present, and future”, provides us with an overview of where we have come from so as to aid in planning for the future.

wounds about the pelvis being caused by arrows, and pelvic and acetabular fractures being caused by heavy stones.

The past In ancient China and Egypt there is abundant evidence for the treatment of orthopedic injuries including fractures of the pelvis. Mummified bodies have been found with overlapping of the pubic symphysis [1]. These may have been caused by some unpleasant injury, perhaps crushed by large stones being used to construct pyramids. However it is more likely that these deformities were caused by the process of mummification and bandaging itself. Perhaps overzealous pelvic sheeting!

In 1066, William the Conqueror arrived in England and defeated King Harold at the Battle of Hastings. William was a warrior who had no interest in medicine and spent his years pacifying the unruly British. It is widely reported that William the Conqueror died of a ruptured testicle but I believe he actually died of the complications of a pelvic injury. Although a ruptured testicle would be acutely painful, it will not in itself lead to death. I believe the sequence of events were as follows: William’s wife became increasingly irritated by his enlarging frame. In 1087, she sent him to Rouen to go on a diet.

On the way he was involved in a skirmish (he could not really resist a fight). In those days saddles had a very high pommel and as his horse stumbled he was thrown against the pommel

In India, surgery was developing with instruments devised to release ligaments, and traction apparatus to reduce dislocations of the hip. In Ancient Greece there are descriptions of

Hippocrates actually classified hip dislocation [2]. He described inward, outward, backward, and forward dislocations of the head of the femur in relation to the pelvis. He devised strategies for relocation, emphasizing the importance of a different technique for each different type of dislocation.

Around the time of the birth of Christ, anatomy became of great interest. Accident surgery had also become very important. Avicenna (980–1087 AD) produced many texts in Arabic describing anatomical structures and he again emphasized the underlying principles of fracture treatment outlined by Hippocrates [3].

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and sustained a symphyseal separation. I often see these in modern day horse riders, particularly in North America where saddles are of a slightly different design than in Europe. This would account for his external injuries which I think were misinterpreted as a testicular rupture. I believe he sustained a symphyseal separation and injury to the genito-urinary tract, probably a urethral rupture. There would have been secondary contamination leading to septicemia and death.

During the Dark Ages, Europe saw very few advances in the specialty of orthopedics and in particular pelvic surgery. The modern specialty was really born with the publication of Malgaigne’s books on fractures and subluxations in 1847 [4].

At the same time in the United Kingdom, Sir Astley Cooper (1768–1841) described various pelvic fractures, making the distinction between marginal stable fractures and unstable pelvic ring injuries. At this stage it should be emphasized that all these observations were made on clinical grounds with no x-rays. For an acute diagnosis to be made there had to be obvious visible or palpable displacement of bones. This is why in Malgaigne’s books and atlas he only describes significantly displaced fractures and dislocations of the pelvis. There is some confusion with modern day surgeons about what precisely a Malgaigne fracture is. I believe if one studies his books closely, he is describing what is now known as bilateral sacral fracture or “jumper’s fracture”. These are the Hshaped double vertical shear fractures that people sustain when they fall or jump from a great height. There are usually saggital transforaminal fractures of the sacrum accompanied by transverse connections with translocation of the sacrum and encroachment of the sacral canal. These injuries are usually complicated by neurological damage. Malgaigne describes these fractures associated with people jumping from buildings that were on fire. He also describes novel techniques for reduction of the fractures with the introduction of large wooden rods into the rectum. The wooden rod would reduce the translated sacral fractures into a better position. However, the technique was usually complicated by gross abdominal distension and he therefore went on to devise silver cylinders with cannulas to allow the escape of air. He records one patient being able to walk home after such treatment after twelve days despite “a little infection”! The modern specialty of acetabular surgery was yet to be born.

With the introduction of x-rays, the subspecialty advanced rapidly and different types of pelvic and acetabular fracture were identified. Albin Lambotte (1866–1955) produced stunning descriptions of techniques for fixing sacral fractures and described the use of sacral bars [5]. He was truly the master of

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all surgeries and significantly advanced the surgery of fracture management. In the UK in 1948, Sir Frank Holdsworth (1904– 1969) produced his paper on dislocations and fracture dislocations of the pelvis [6]. He was a student at Cambridge and St George’s Hospital, Hyde Park. He undertook a number of junior positions at St George’s before becoming the first orthopedic specialist in Sheffield in 1937. His paper studied 50 patients and made key observations—including the dangers of death by

bleeding and the complication of genitor-urinary injury. He concluded that sacral iliac dislocation was an evil injury with most patients suffering chronic permanent agonizing pain whereas patients with ilio-sacral fracture dislocations (crescent fractures) had a better overall outcome.

In the 1950s and 1960s, other than pelvic slings, the only surgical treatment recommended for unstable pelvic injuries were forms of external fixation. These became the gold standard treatment of such injuries. George Pennal (1913–1976) working in the University of Toronto Anatomy Department, began to identify subsets of pelvic fractures including lateral compression injuries, vertical shear forces, and open book type fractures. The study of the biomechanics led him to produce a classification which was later further modified by Tile.

Meanwhile in Paris in the late 1950s and 1960s, Robert Judet began attempting to treat displaced acetabular fractures surgically. He felt that the outcomes with displaced acetabular fractures following conservative treatment were unacceptable. He identified certain subsets of acetabular fractures that did not do well with conservative treatment. These included fractures that involved the tectum or roof and those fractures where the hip was unstable. He described ten classic fracture patterns (five basic and five complex). Judet also developed

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many surgical approaches, particularly the ilio-inguinal approach, for treatment of anterior acetabular injuries. His work was continued by his student Emile Letournel who diligently collected data, listed complications, and educated a large group of surgeons including Claude Martinbeau, Joel Matta, Geoffrey Mast, Keith Mayo, and Eric Johnson. Other surgeons visited Paris regularly, including David Helfet and Roy Moed. Meanwhile in Toronto, Marvin Tile continuing Pennal’s work, published the classification of pelvic fractures in the Journal of Bone & Joint Surgery (1986), and brought the specialty together with his comprehensive book entitled “Fractures of the Pelvis and Acetabulum”. There have now been three editions of Tile’s book (1984, 1995, and 2003).

With Tile’s teaching and the Sunnybrook fellowships, the practice of pelvic and acetabular surgery has been advanced and spread across the world. I was fortunate enough to be one of his fellows in 1987. His books complement the equally brilliant text on fractures of the acetabulum produced by Emile Letournel.

The present Presently in the developed world, a full time job as a trauma surgeon is not considered compatible with a good lifestyle. The hours can be inconvenient and other subspecialties within orthopedics pay much more handsomely. For pelvic and acetabular fracture surgery to provide the greatest benefit to the injured patient in all countries, certain issues need to be urgently addressed. By providing a good pelvic fracture service the trauma system as a whole will benefit.

Trauma hospitals are struggling financially and this is at least partly due to the unsophisticated coded systems that are used to define activity and thus funding. For example, there are over 17 different ICD10 codes for pelvic fractures and over 40 codes relevant to the pelvis in the OPCS system. Better coding systems need to be developed in order to allow prompt payment for the treatment of trauma patients.

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However, some units, particularly within the USA, are avoiding treating uninsured trauma patients as they drain resources. This is known in the United States as ‘dumping’. These issues are not only causing clinical problems but also have a major detrimental effect on training.

An example of these inefficiencies was highlighted in the United Kingdom in 2002. After a frustrating year of delays in the definitive treatment of pelvic and acetabular patients I went public with an audit that demonstrated that, within my locality, it was 12 days between injury and a definitive surgery for a pelvic and acetabular fracture. This audit led to a number of meetings with healthcare providers resulting in the introduction of a special tariff for definitive pelvic and acetabular fracture reconstruction. It was felt that if there was a better financing capability, the delay would be reduced. This in some ways helped the situation as trauma units started receiving more money for the treatment of pelvic fractures. However other injuries eg, open fractures, are still poorly resourced and the trauma units are still struggling. Unfortunately a subsequent audit in my unit between June 2004 and June 2005 showed that the mean delay between injury and definitive surgery still remains 12.6 days. The steady increase in local trauma that remains underfunded has absorbed the extra resource earmarked for pelvic fractures. Other meetings are going on in order to try and further rectify this problem. These problems I believe are mirrored across Europe and North America.

What are the solutions?

We must make trauma care attractive as a career to recruit young doctors, make sure they are paid appropriately, and that they have good working conditions. We need to apply political pressure and lobby our political masters.

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We need to link up with our hip revision surgical colleagues to deal with this influx of osteoporotic acetabular trauma. In the acute phase, reconstruction is sometimes impossible or fruitless. It is now recognized that techniques, other than reconstruction, are available and are indicated when fractures are very comminuted or bone quality is poor. Within our unit at St George’s, there is close liaison between the fracture group and the hip reconstruction revision group.

There is some good news, certainly within the UK. We have over a dozen specialist pelvic units with fellowship trained surgeons. The new tariff will help to fund these units. Regular courses are run across the world and we recently completed another successful course in September 2006. The bad news is that these unacceptable delays remain and the pelvic story is somewhat deflected away from the fact that trauma systems are failing across the world. We are also being flooded with an increasing number of osteoporotic traumas associated with our ageing population.

We need to collect data. With this in mind, the European Pelvic Association of Surgeons (EPAS) has been formed. This will give us teeth. We also need to evolve better coding systems and continue educating ourselves, the public, and the politicians.

The future

The immediate future of pelvic and acetabular surgery, in my opinion, should mainly focus on organizational changes. Systems need to be defined. Education needs to continue. Trauma, and particularly pelvic and acetabular surgery, needs to be brought to the forefront and inadequacies of our systems need to be highlighted to the politicians and the public. We should continue developing fine instruments and strive to develop new techniques to make the surgery of pelvic and acetabular fractures safer. With this in mind, computers will come to the forefront. Image guided surgery combined with sophisticated preoperative imaging will allow more focused treatment and less extensive incisions which are associated with a high complication rate. These advances, however, will not be possible if cases are delayed and callus forms around fracture surfaces. Indirect reductions are impossible under these circumstances. It would be an advantage to have new gadgets eg, talking drills that tell you the length of the screw, self-tapping biodegradable implants, precontoured plates, fracture glue, and some form of bone restorer.

In the more distant future, robotic surgery may become a possibility. On the biological front, there is encouraging work on cartilage replacement and nerve regeneration. We are still confronted on a regular basis with young patients with large areas of primary articular cartilage damage occurring at the time of an acetabular injury. Primary articular cartilage loss is irreversible and until we have a system of replacing it, we will not achieve good long term outcomes following a reconstruction of such injuries. One of the more devastating complications following a pelvic fracture is lumbo-sacral nerve injury.

Young men are rendered impotent and women suffer neurological pelvic floor symptoms. In the future we may be able to replace areas of injured nerve thus reversing neurological damage, impotence, and pelvic floor weakness.

In the more distant future spare part surgery may become an option. New acetabular sockets may be available and perhaps whole sacral units with nerves attached may be pulled “off the shelf”.

If one looks at a UK £2 coin you will see written around the edge the saying “standing on the shoulders of giants”. Our understanding and advancement of pelvic and acetabular surgery relies on the work of our forefathers. I am privileged to have stood on the shoulders of Marvin Tile and will always be grateful for the teaching and advice he has given me.

Bibliography 1 Wenz W, et al (1975) Blick in die Vergangenheit. “Ägyptische Mumie im Röntgenlicht”. Adiologe; 125: 45–49.

2 Lithington ET (1828) Hippocrates. London. Loeb classic library Vol III. 3 Varusis Amidas (2001) History of Orthopaedics. Athens.

4 Malgaigne JF (1847) Traite des fractures et des luxations, 2 volumes.

5 Lambotte A (1913) Chirurgie Oreratoire du Fractures. Paris, Masson et Cie. 6 Holdsworth FW (1948) “Dislocations and Fracture Dislocations of the Pelvis”. J Bone Joint Surg Br; 30:461.

Martin Bircher, MD

United Kingdom linda.haylor@stgeorges.nhs.uk

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Steven L Frick and Virginia Casey

AO Debate Acute on chronic, unstable slipped capital femoral epiphysis Acute on chronic, unstable slipped capital femoral epiphysis is a common condition that faces the orthopedic surgeon in the emergency department or the clinic. For many years, either in situ pinning or gentle closed reduction and in situ pinning has been recommended. Recently, with a newer understanding of the hip blood supply and the concept of femoral acetabular impingement as a cause for osteoarthritis, interest in the possibility of open reduction and pinning was renewed. This debate will explore the two options.

The case presented of an acute on chronic SCFE is better discussed in terms of physeal stability, as Loder has clearly defined unstable SCFE (patient unable to bear weight) as the major risk factor for osteonecrosis (ON) [2]. The classification based on timing of symptoms previously used in the literature is helpful in understanding the pathoanatomy of SCFE, which differs from femoral neck fractures as the proximal femur remodels in response to the slip. The callus that thus forms posteromedially has important treatment implications.

Case presentation A 12-year-old male was presented to the emergency department by ambulance after tripping and falling in the playground at school. He was unable to get up and could not bear weight on his left lower extremity. He reported 3 months of left knee pain and occasional limping prior to the fall. He had an unstable slipped capital femoral epiphysis on the left that was completely displaced (Fig 1a–b).

Traditional teaching is that reduction of SCFE is dangerous and may cause ON. The literature is unclear if this applies to stable slips, unstable slips, or both. Standard treatment of unstable SCFE frequently describes unintentional reduction during positioning prior to internal fixation in situ, and does not recommend a formal reduction maneuver. Practitioners are cautioned to avoid forceful manipulations and reductions that may cause ON. An anatomical explanation for the increased risk would be stretching the posteromedial retinacular vessels over the slip callus.

What is the best surgical treatment for this patient? Is it emergent or urgent? What is his risk of osteonecrosis? What is the role of intracapsular hematoma as a possible cause of osteonecrosis?

Steven L Frick Open reduction for acute on chronic slipped capital femoral epiphysis The recommended treatment for slipped capi-

tal femoral epiphysis (SCFE) has for years been pinning in situ, regardless of the severity of the slip, as retrospective long term follow-up studies reported higher complications and poorer results with reduction or realignment procedures [1].

Major adverse sequelae of SCFE are ON, poor motion, and early arthritis. Chondrolysis is less common in the era of cannulated screw fixation. Loder reported an ON rate of 50% in unstable slips, and other reports cite a 10–50% risk. An arteriographic study of 5 unstable SCFE describes loss of the dominant vessel supplying the epiphysis in 3 of the 5 when the epiphysis is displaced, and in one case demonstrated restoration of flow in this vessel after reduction. The study concluded that in some unstable slips the vascular injury occurs at the

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Fig 1a–b Unstable slipped capital femoral epiphysis.

c b

time of injury, and that reduction does not necessarily contribute to the risk of ON [3]. Growing evidence shows that b residual anatomic abnormalities predispose patientsc to early hip osteoarthritis (OA)—how much deformity is acceptable, and how much remodeling potential a given individual has are not yet clearly defined. For SCFE, long term studies (Weinstein) state that deformity can be tolerated well.

The idea that reduction of an unstable SCFE is dangerous is not supported by more recent reports. Practically, some unstable slips cannot be pinned in situ as the neck is completely displaced from the epiphysis. After 40 years of experience, two centers reported only a 13% incidence of ON following early manipulative reduction of acute SCFE, although not all had open procedures or capsular decompression. Gordon et al recommend early reduction of unstable slips with arthrotomy (decompression) and cannulated screw fixation to lessen the risk of ON. Open reduction of unstable SCFE has been advocated [4, 5], with the advantage of decompressing any intracapsular hematoma, and allowing some direct assessment of reduction. The disadvantage is that closed reductions and open anterior approaches do not allow visualization and removal of posteromedial callus. This leads to the recommendation to reduce unstable slips to their “stable” or “preacute” position—ie, to the position that will not stretch the capsular vessels over the callus. To decrease the risk of ON, the surgeon accepts residual deformity that may predispose the patient to poor motion and early OA.

Leunig et al reported utilization of the Ganz surgical dislocation approach for SCFE in an article that primarily described the intraarticular changes noted in SCFE patients intraoperatively consistent with FAI. No patient developed ON (3 had acute on chronic SCFE), and the research from this group has led others to begin using the surgical dislocation approach to address SCFE pathology, including the unstable slip. If this approach can result in a decreased incidence of ON following unstable SCFE, it may become the standard treatment method as it allows restoration of normal anatomy that should also improve motion and lessen the risk of early OA. Surgical dislocation of the hip allows circumferential visualization of the femoral head and neck, with the piriformis and importantly obturator externus tendons intact to protect the vascular supply. The exposure of the femoral neck must be done with care and must not damage the vessels within the periosteum and capsular layer posteromedially. This exposure affords visualization of the remodeling and callus along the posteromedial femoral neck, which can then be removed to allow complete reduction of the slip deformity without stretching the vessels over the callus and compromising perfusion. The position of the head on the neck can also be directly visualized, lessening dependence on radiographic assessments of head-neck alignment. It still remains to be seen whether or not this approach can eliminate ON, or if the injury to the blood supply can occur at the time of initial displacement and be unrecoverable.

Ganz et al [6] have increased our knowledge and understanding of the blood supply to the femoral head, and also of the effects of proximal femoral deformity on hip joint longevity and function, with an emphasis on femoroacetabular impingement (FAI) as a cause of early OA of the hip. The detailed studies of proximal femoral arterial anatomy [7], development of an anatomically based surgical approach and clinical series of safe surgical dislocation of the hip [8] offer a new way to address SCFE. The potential adverse effect of intracapsular hematoma on femoral head blood flow has also been confirmed, showing that increased intracapsular pressure can decrease perfusion to the epiphyseal region and may contribute to ON following femoral neck trauma (Ng and Cole).

Recent literature supports reduction of unstable SCFE and stable fixation with decompression of any intracapsular hematoma. The options for achieving this are closed reduction and fixation followed by capsulotomy, open reduction via an anterior approach, or surgical dislocation. Follow-up studies (>2 years) are needed to document that surgical dislocation can be done safely in patients with unstable SCFE.

Virginia Casey Closed reduction and in situ pinning

Slipped capital femoral epiphysis (SCFE) is a common disorder that affects 0.2 to 10 adolescents per 100,000. It is characterized by displace-

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Fig 2a–b X-rays after 4 weeks showing no change in alignment of the hip.

c a

b

ment of the femoral head on the metaphysis causing pain and deformity. SCFE can be classified based on duration of the symptoms (more traditional classification) or on physeal stability as described by Loder. Classification of symptoms based on chronicity includes acute, chronic, and acute on chronic categories. Older literature utilized this classification for data collection. More recent literature characterizes slips according to physeal stability, which has been found to be the major determinant for the risk of developing osseous necrosis.

Reduction that is done with positioning and is “incidental” is thought to reduce the acute component of an acute on chronic slip. This allows for some deformity correction without stretching the blood supply over the callous which forms on the posterior-medial femoral neck in chronic SCFE. Peterson demonstrated no increase in incidence of osseous necrosis with closed reduction of acute SCFE. However, Tokmakova found an increased risk of osseous necrosis even with a partial reduction when compared to pinning in situ.

Treatment of chronic stable SCFE is not controversial. These patients have no risk of osseous necrosis and do well with in situ pinning [2, 9, 10]. However, significant controversy remains for the optimal treatment of a child with an unstable SCFE (patient unable to bear weight) be it acute or acute on chronic in nature.

O’Brien and Jones have shown that even in patients with moderate to severe SCFE there is extensive remodeling of the deformity [11]. In these patients there was resorption of the anterolateral femoral neck allowing near normal hip range of motion with the exception of a loss of 5–20° of internal rotation in some patients. Those patients with incomplete remodeling are candidates for a femoral osteotomy.

There are several factors to consider when treating unstable/ acute slipped capital femoral epiphysis. The most important is the avoidance of osseous necrosis. SCFE with osseous necrosis is more likely to have a poor functional outcome with the need for subsequent surgery. Factors that may be associated with the development of osseous necrosis include physeal stability, slip severity, age of the patient, timing of fixation, number of screws/pins for fixation, and reduction of the deformity.

Of these factors, the only predictor of osseous necrosis that is consistent in the literature is physeal instability. The literature cites a 10–50% osseous necrosis rate in unstable SCFE. Few studies evaluate the treatment of SCFE. The papers that do assess treatment are limited by small patient numbers, retrospective designs, and significant treatment variability.

Treatments studied include: casting, in situ pinning, incidental reduction and pinning, formal closed reduction, pinning with or without preoperative traction, and open reduction with or without a number of different femoral osteotomies.

The most common treatments cited in a recent survey of the POSNA membership revealed that 84% perform in situ pinning after positioning or incidental reduction, 11.8% pin after a formal reduction, and 3% perform an open reduction.

The long term literature on SCFE is favorable for the hips with mild to moderate deformity and no osseous necrosis [1]. The hips with severe deformity have increasing hip pain with time. Those hips with osseous necrosis tend to do poorly. Thus treatment is aimed at decreasing rates of osseous necrosis while minimizing deformity. The literature does not support an obvious best treatment option for unstable SCFE. Open treatment using the Ganz surgical dislocation approach may prove to decrease the rates of osseous necrosis and restore normal anatomy, though this is not yet supported in the literature.

In situ pinning and incidental reduction with pinning are percutaneous techniques that are not technically difficult.

The known long term results of these treatments are as good if not better than open reduction techniques that are technically more challenging and not as amenable to being performed by general orthopedic surgeons. While time may prove that new open reduction techniques are successful in the prevention of osseous necrosis, current literature supports the use of less invasive techniques and should be the mainstay of treatment for unstable SCFEs.

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Fig 3a–b Osteonecrosis with collapse of the femoral epiphysis.

c b

Outcome The patient was taken urgently to the operating room and underwent reduction to the “preacute” position by placing him in traction on a fracture table, under fluoroscopic guidance. The proximal femur was stabilized with a single 7.3 mm cannulated screw, and the hip was aspirated to decompress the intracapsular hematoma. The patient was kept on crutches with limited weight-bearing for 4 weeks, and x-rays

then showed no change in alignment of the hip and good position of the screw (Fig 2a–b).

The patient was then lost to follow-up. He returned at 11 months after his surgery complaining of left groin pain and a limp, and x-rays at that time showed osteonecrosis with collapse of the femoral epiphysis (Fig 3a–b).

Steven L Frick, MD

Pediatric Orthopaedics Residency Program Director Department of Orthopaedic Surgery Carolinas Medical Center Charlotte, NC, USA steven.frick@carolinashealthcare.org

Virginia Casey, MD

Pediatric Orthopaedic Surgeon OrthoCarolina Charlotte, NC, USA virginia.casey@orthocarolina.org

Bibliography 1 Carney BT, Weinstein SL, Noble J (1991) Long-term follow-up of slipped capital femoral epiphysis. J Bone Joint Surgery Am; 73(5):667–674.

2 Loder RT, Richards BS, Shapiro PS, et al (1993) Acute slipped capital femoral epiphysis: the importance of physeal stability.

J Bone Joint Surg Am; 75:1134–1140.

3 Maeda S, Kita A, Funayama K, et al (2001) Vascular supply to slipped capital femoral epiphysis. J Pediatr Orthop; 21(5):664–667.

4 Parsch K, Zehender H, Buhl T, et al (1999) Intertrochanteric corrective osteotomy for moderate and severe chronic slipped capital femoral epiphysis. J Pediatr Orthop B; 8(3):223–230.

5 Aronson J, Tursky EA (1996) The torsional basis for slipped capital femoral epiphysis. Clin Orthop Relat Res; (322):37–42.

6 Ganz R, Parvizi J, Beck M, et al (2003) Femoroacetabular impingement: a cause for osteoarthritis of the hip.

Clin Orthop Relat Res; (417):112–120.

7 Gautier E, Ganz K, Krugel N, et al (2000) Anatomy of the medial femoral circumflex artery and its surgical implications. J Bone Joint Surg Br; 82(5):679–683.

8 Beck M, Kalhor M, Leunig M, et al (2005) Hip morphology influences the pattern of damage to the acetabular cartilage: femoroace-tabular impingement as a cause of early osteoarthritis of the hip. J Bone Joint Surg Br; 87(7):1012 –1018.

9 Kennedy JG, Hresko MT, Kasser JR, et al (2001) Osteonecrosis of the femoral head associated with slipped capital femoral epiphysis.

J Pediatr Orthop; 21(2):189–193.

10 Tokmakova KP, Stanton RP, Mason DE (2003) Factors influencing the development of osteonecrosis in patients treated for slipped capital femoral epiphysis. J Bone Joint Surg; 85-A(5):798–801.

11 O’Brien ET, Fahey JJ (1997) Remodeling of the femoral neck after in situ pinning for slipped capital femoral epiphysis.

J Bone Joint Surgery Am; 59(1):62–68.

Suggestions for further reading Aronsson DD, Loder RT (1996) Treatment of the unstable (acute) slipped capital femoral epiphysis. Clin Orthop Relat Res; (332):99–110.

Gordon JE, Abrahams MS, Dobbs M, et al (2002) Early reduction, arthrotomy, and cannulated screw fixation in unstable slipped capital femoral epiphysis treatment. J Pediatr Orthop; 22(3):352–358.

Mooney JF III, Sanders JO, Browne RH, et al (2005) Management of unstable/acute slipped capital femoral epiphysis: results of a survey of the POSNA membership. J Pediatr Orthop; 25(2):162–166.

Notzli HP, Siebenrock KA, Hempfing A, et al (2002) Perfusion of the femoral head during surgical dislocation of the hip. Monitoring by laser Doppler flowmetry. J Bone Joint Surg Br; 84(2):300–304.

Peterson MD, Weiner DS, Green NE, et al (1997) Acute slipped capital femoral epiphysis: the value and safety of urgent manipulative reduction. J Pediatr Orthop; 17(5):648–654.

Rattey T, Piehl F, Wright JG (1996) Acute slipped capital femoral epiphpysis. Review of outcomes and rates of avascular necrosis.

J Bone Joint Surgery Am; 78(3):398–402.

AODIALOGUE 1/07

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Sao Paulo, Brazil

AO Hand Course June 28–30, 2007

For additional AO courses and events, please visit:

www.aofoundation.org

Basic Principles and Techniques of Operative Fracture Management Course for Residents

Sapporo, Japan

• 11th AO Principles Course • AO Course on Principles of Operative Fracture Management for ORP August 24–26, 2007