J Am Acad Orthop Surg, Vol 16, No suppl_1, July 2008, xii-xv.
© 2008 the American Academy of Orthopaedic Surgeons
Seppo Santavirta: The Life and Work of an Orthopaedic Surgeon and Scientist. A Tribute From His Friends
Yrjö T. Konttinen, MD, PhD,
Stuart B. Goodman, MD, PhD and
Timothy Wright, PhD
Dr. Konttinen is Professor of Medicine, University of Helsinki, Helsinki, Finland. Dr. Goodman is Robert L. and Mary Ellenburg Professor of Surgery, and Professor, Department of Orthopaedic Surgery, Stanford University Medical Center, Stanford, CA. Dr. Wright is F. M. Kirby Chair of Orthopaedic Biomechanics, Hospital for Special Surgery, New York, NY.
Dr. Goodman or a member of his immediate family has received research or institutional support from Zimmer and is a member of the US Food and Drug Administration Panel for Orthopaedic and Rehabilitation Devices, AAOS Biological Implants Committee, National Institutes of Health Tissue Engineering Study Section, and he serves as a consultant to Zimmer, Accelalox, Biomimedica, Biomimedic Therapeutics, StemCor, and Charter Life Sciences. Dr. Wright or a member of his immediate family has received research or institutional support from Zimmer, Synthes Spine, and Smith & Nephew, and has received royalties from Mathys. Neither Dr. Konttinen nor a member of his immediate family has received anything of value from or owns stock in a commercial company or institution related directly or indirectly to the subject of this article.
This supplement is dedicated to the late Professor of Orthopaedic Surgery, Seppo Santavirta, MD, PhD, who was one of the world’s premier researchers in the field of implant wear and loosening. The supplement is a collaborative work based on lectures, discussions, and other presentations given at the 2007 AAOS/National Institutes of Health–sponsored symposium titled Osteolysis and Implant Wear: Biological, Biomedical Engineering and Surgical Principles, held in Austin, Texas, November 9-11, 2007, and dedicated to the memory of Professor Santavirta. These opening remarks are written by his close friends as well as by his beloved wife, Nina, and sons, Torsten and Robin. Professor Santavirta was always invited to and actively participated in the previous Implant Wear symposia, and he proved to be an inspiration for clinicians, researchers, and educators alike. Seppo, always healthy, robust, and an accomplished sportsman, passed away after a short illness on June 22, 2005, just a few days before the Magic Midsummer Night Eve with white nights and myriads of flowers blooming in the woods on his summer island, Högsåra, in the Archipelago of the Finnish Gulf.
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Seppo’s Young Years
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Seppo Santavirta was born into a physician’s family on December 5, 1945, in postwar Finland. He lost both of his parents when he was still in school. Seppo volunteered to join the army, completing his service at the age of 18 as its youngest second lieutenant. He then decided to follow in his father’s footsteps and moved to Zürich, Switzerland, to study medicine. During his time at medical school and as a young physician, he also competed at an international level in speed skating in sprinter distances (Figure 1).
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The Mature Clinician-Scientist
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After specializing in orthopaedics and completing a second doctoral thesis in 1979 at the University of Helsinki on "Tourniquet Ischemia," Seppo began his studies of the synovial-like interface membrane around loose total hip replacements. He described aggressive granulomatosis in clinical and radiologic terms, and began collecting tissue samples from his grateful and cooperative patients to characterize the underlying histopathologic processes. In a widely cited series of works,1-3 he described the host response to implant-derived wear debris as a monocyte/macrophage, giant cell, and granuloma-dominated foreign body reaction (Figure 2). He concluded that these cells were responding to implant-derived particles, and he wanted to understand the biologic processes in which these cells were involved.
One of Seppo’s cardinal thoughts was that the foreign body response resulted in the release of proinflammatory cytokines and other tissue-destructive mediators produced in the joint. Through microscopy, he had personally seen implant-derived particles in tissues from his revision cases. He entertained the idea of an "extended joint space," which developed gradually around the implant, loosening it from its surrounding bone. This expansion of the effective joint space was thought to develop as a result of micromotion at the implant-host interface (due to the mismatch in mechanical stiffness between the metallic implant stem and host bone), synovial fluid pressure waves (driven by cyclic mechanical loading of the fluid-filled prosthetic joint during walking), and, in particular, proteinases weakening the implant-host interface.
Because this tissue-destructive action was apparently directed against the fibrous implant capsule developing around implants fixed to bone, Seppo became particularly interested in matrix metalloproteinases (MMPs) and serine proteinases. They form the neutral endoproteinases, which do not act intracellularly in phagolysosomes but are produced for export to act in the neutral pH of the extracellular space. Various collagenolytic enzymes were described in the pseudosynovium of the prosthetic joint and in the synovial membrane-like interface. These papers were often authored in cooperation with distinguished names in the field, such as Seppo’s work on collagenase-1 with Professor Arthur Z. Eisen4 and Professor Harald Tschesche.5 Later, Seppo described collagenase-3 in loosening together with its discoverer, Professor Carlos Lopéz-Otín,6 and membrane type 1–MMP with its discoverer, Professor Motoharu Seiki.7 This work culminated in articles describing all 16 MMPs known at that time around loose hip implants.8
This period was characterized by an extraordinary amount of research, which is best exemplified in a supplement to Acta Orthopaedica containing the summary of an honors thesis by Dr. Michiaki Takagi, one of the many international visitors and protégées trained in Seppo’s unit.9 As a result of his scientific accomplishments and overall leadership, Dr. Seppo Santavirta was unanimously chosen to become Professor and Chair of Orthopaedics and Traumatology at the University of Helsinki, a position he assumed in 1996.
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Professor Santavirta
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Seppo’s selection as Professor forced a move from his beloved Invalid Foundation to the Helsinki University Central Hospital. Organizational restructuring was underway at the hospital, but through it all Seppo, his close friends, and the TULES (Musculoskeletal Diseases and Biomaterials Research) group continued their work, leading them to say, "Dogs are barking, but the caravan moves on!" Within his collaborative group, they followed Alexander Dumas’ famous dictum: "One for all, and all for one!"
Seppo was never afraid of new ideas and discoveries. Upon discovery of cathepsin K, an acidic endoproteinase and effective collagenase, work was begun to measure the pH around loosening implants and to detect and analyze cathepsin K in such tissues at the messenger RNA, enzyme protein, and activity level.10 Seppo concluded that foreign particles apparently attract and activate macrophages so that they begin producing tissue-destructive proteinases, leading to other adverse host responses, as described in a thesis completed by Dr. Tian-Fang Li under Seppo’s tutelage in 200011 and in cooperative work with Professor Enrique Gomez-Barrena.12
But how can one eliminate adverse reactions to implants? Seppo’s orthopaedic experience led him to the idea of a wear-resistant, noncorrodible surface coating. He soon found a group of physicists at the van de Graaff nuclear acceleration laboratory (Diamond Group, University of Helsinki) who were working with plasma acceleration methods that could produce thick-film amorphous diamond coatings (Figure 3). The technique was developed in cooperation with Professor Asko Anttila, who led the Diamond Research Group at the University of Helsinki.13-15 Seppo was particularly proud of his third doctoral thesis from Kuopio University on this topic, titled "Compatibility of the Totally Replaced Hip: Reduction of Wear by Amorphous Diamond Coating."16 Studying the physics behind the coating technology was hard work, but that made it all the more rewarding.
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Figure 3 Diamond-coated femoral component of a total hip implant (top) and knee prosthesis component (bottom).
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When looking for commercial partners willing to apply this coating in metal-on-metal bearings, two new hypotheses emerged. Seppo had already noticed that metal-on-metal bearings produced very low volumetric wear but huge numbers of particles, which were rarely seen in tissue-retrieval analysis. These small, submicroscopic metallic particles were associated with a chronic foreign-body reaction that was sometimes different than previously seen and constituted a delayed hypersensitivity reaction as described by the late Professor Hans-Jorg Willert.17 Thus the first hypothesis was developed: endocytosis via phagocytosis is usually coupled with inflammation (as in particle-induced disease [exception, apoptosis], whereas endocytosis via pinocytosis (cells "drinking" [exception, macropinocytosis] is usually not accompanied by inflammation.
The second inspired hypothesis was related to the hidden "septic" component in so-called aseptic loosening. This was envisioned to be mediated via structural microbial components (ie, pathogen-associated molecular patterns [PAMPs]) (or endogenous alarmins) recognized by pattern-recognizing receptors such as toll-like receptors (TLRs). PAMPs (TLR ligands) were thought to be hidden in the biofilm, living vita minima (keeping a very low profile) instead of displaying their pathogenetic virulence that exposes them to host and foreign defenses (eg, by neutrophils and antibiotics). This hypothesis is being tested in the laboratory by the next generation of young students, such as Guofeng Ma, Praseet Poduval, Vesa-Petteri Kouri, Jukka Pajarinen, and Jaakko Levón, as well as by senior visiting scientists Dr. Daisuke Ogino (Mathematics) and Professor Orlando Sanchez-Munoz (Physics).
Since Seppo’s sudden and unexpected death, the orthopaedic division of the TULES group has been supervised by Clinical Lecturer Dr. Jari Salo, and Seppo’s important research will continue in close cooperation with Ilkka Kiviranta, Seppo’s successor as the new Professor and Chair.
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Educational and Other Contributions to the Field
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In addition to his clinical and scientific achievements, Seppo was a great educator, supervising many doctoral students and foreign visitors. His group has hosted scientists from 24 countries, including China, Japan, India, Libya, Turkey, Estonia, and Greece. Seppo was a member of the editorial and research boards of numerous scientific journals, including the The Journal of Bone and Joint Surgery, British volume. Perhaps his most valued engagement was as a Co-Editor with Acta Orthopaedica, where he had particularly close ties to the late Professor Göran Bauer. He was the secretary, then vice-chairman, and, at the time of his death, chairman of the National Center of Excellence in Biomaterials and Tissue Engineering of the Academy of Finland from 2000 to 2005. He hosted Professor Timothy Wright (New York, NY) and Professor Michael Silberman (Haifa, Israel) as external evaluators every year. He was on the Board of the National PhD Graduate School of the Ministry of Education, which hosted many domestic and foreign doctoral students. He was the Chairman of the European Orthopaedic Research Society Congress held in Helsinki in 2003. He also had the honor to edit special issues published in Clinical Orthopaedics and Related Research, "Biocompatibility and Host Response in Total Hip Replacement" in 1998,18 and "Material and Tribology in Total Hip Replacement" in 2005.19 Seppo was also one of the two Masters of Ceremonies in the famous "Science Beer" meetings of the TULES group, where good scientific presentations and discussions, brainstorming, and, of course, consumption of large quantities of beer continued late into the night.
Seppo’s life was crowned by his marriage to Dr. Nina Santavirta. Together, they raised two talented sons, Torsten Osmo Olav (born in 1977) and Robin Sebastian (born in 1980). Seppo often joked that behind every successful man is a surprised woman. He surprised his wife by expanding into the diamond business, producing high-quality diamonds from industrial graphite. Seppo was also an expert on Finnish and Nordic arts and antiques, and was often seen at exhibitions and in art and antique shops. He shared hobbies, such as exploration of the Finnish archipelago, sailing, and bicycling, with his sons, who by the age of 10 were already so familiar with his work that they would call him if a letter came from the The Journal of Bone and Joint Surgery or Acta Orthopaedica to tell him that a letter from "Bone" or "Acta" was waiting at home. Seppo’s heritage is written in the orthopaedic literature.
Seppo was a big, strong man who, after winning many medals for sprinter distances in speed skating, won medals in sprint distances in velodrome bicycling. Perhaps because he was not threatened by anyone, he was a calm and peaceful man who promoted peace and cooperation. He often talked of how important it is that people from different countries work together toward a common goal and in good spirit; it is difficult to dislike anyone with whom you have become an intimate friend and colleague. His legacy continues in a vital and substantial way in his international TULES group.
Seppo’s great intelligence, inquisitiveness, enthusiasm, collaborative spirit, and long-lasting friendship will always be remembered and will continue to shape the lives of his family and those of us who were fortunate to know him.
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Figures
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References
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- Santavirta S, Konttinen YT, Bergroth V, Eskola A, Tallroth K, Lindholm TS: Aggressive granulomatous lesions associated with hip arthroplasty: Immunopathological studies. J Bone Joint Surg Am 1990; 72:252-258. [Abstract/Free Full Text]
- Santavirta S, Hoikka V, Eskola A, Konttinen YT, Paavilainen T, Tallroth K: Aggressive granulomatous lesions in cementless total hip arthroplasty. J Bone Joint Surg Br 1990; 72:980-984. [ISI][Medline]
- Santavirta S, Konttinen YT, Hoikka V, Eskola A: Immunopathological response to loose cementless acetabular components. J Bone Joint Surg Br 1991; 73:38-42. [ISI][Medline]
- Santavirta S, Sorsa T, Konttinen YT, Saari H, Eskola A, Eisen AZ: Role of mesenchymal collagenase in the loosening of total hip prosthesis. Clin Orthop Relat Res 1993; 290:206-215. [Medline]
- Takagi M, Konttinen YT, Kemppinen P, et al: Tissue inhibitor of metalloproteinase 1 and collagenolytic and gelatinolytic activity in loose hip endoprostheses. J Rheumatol 1995; 22:2285-2290. [ISI][Medline]
- Imai S, Konttinen YT, Jumppanen M, et al: High levels of expression of collagenase-3 (MMP-13) in pathological conditions associated with a foreign body reaction. J Bone Joint Surg Br 1998; 80:701-710. [Medline]
- Konttinen YT, Ceponis A, Takagi M, et al: New collagenolytic enzymes/cascade identified at the pannus-hard tissue junction in rheumatoid arthritis: Destruction from above. Matrix Biol 1998; 17:585-601. [ISI][Medline]
- Takei I, Takagi M, Santavirta S, et al: Messenger ribonucleic acid expression of 16 matrix metalloproteinases in bone-implant interface tissues of loose artificial hip joints. J Biomed Mater Res 2000; 52:613-620. [ISI][Medline]
- Takagi M: Neutral proteinases and their inhibitors in the loosening of total hip protheses. Acta Orthop Scand Suppl 1996; 271:3-29. [Medline]
- Konttinen YT, Takagi M, Mandelin J, et al: Acid attack and cathepsin K in bone resorption around total hip replacement prosthesis. J Bone Miner Res 2001; 16:1780-1786. [ISI][Medline]
- Li T-F: Extracellular and Pericellular Matrix Proteins in the Synovial Membrane-Like Interface Tissue From Aseptic Loosening of Total Hip Replacement [thesis]. Helsinki, Finland: Helsinki University, 2000.
- Santavirta S, Takagi M, Gómez-Barrena E, et al: Studies of host response to orthopedic implants and biomaterials. J Long Term Eff Med Implants 1999; 9:67-76. [ISI][Medline]
- Anttila A, Lappalainen R, Heinonen H, Santavirta S, Konttinen YT: Superiority of diamondlike carbon coating on articulating surfaces of artificial hip joint. New Diamond and Frontier Carbon Technology 1999; 9:283-288.[ISI]
- Lappalainen R, Selenius M, Anttila A, Konttinen YT, Santavirta SS: Reduction of wear in total hip replacement prostheses by amorphous diamond coatings. J Biomed Mater Res B Appl Biomater 2003; 66:410-413. [Medline]
- Santavirta SS, Lappalainen R, Pekko P, Anttila A, Konttinen YT: The counterface, surface smoothness, tolerances and coatings in total joint prostheses. Clin Orthop Relat Res 1999; 369:92-102. [Medline]
- Santavirta S: Compatibility of the totally replaced hip: Reduction of wear by amorphous diamond coating. Acta Orthop Scand Suppl 2003; 74:1-19. [Medline]
- Willert HG, Buchhorn GH, Fayyazi A, et al: Metal-on-metal bearings and hypersensitivity in patients with artificial hip joints: A clinical and histomorphological study. J Bone Joint Surg Am 2005; 87:28-36. [Abstract/Free Full Text]
- Santavirta S (ed): Symposium: Biocompatibility and host response in total hip replacement. Clin Orthop Relat Res 1998; 352:2-127. [Medline]
- Santavirta S, Goodman SB (eds): Symposium: Materials and tribology in total hip replacement. Clin Orthop Relat Res 2005; 430:1-116. [Medline]
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Seppo's Young Years
The Mature Clinician-Scientist
