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on the Horizon From the ORS

Anderson, Donald D. PhD; Thomas, Thaddeus P. PhD; Frank, Matthew C. PhD; Marsh, Lawrence J. MD; Brown, Thomas D. PhD; Kim, Hubert MD, PhD

JAAOS - Journal of the American Academy of Orthopaedic Surgeons: October 2011 - Volume 19 - Issue 10 - p 644–647

Topics from the frontiers of basic research presented by the Orthopaedic Research Society.

From the Departments of Orthopaedic Biomechanics Laboratory (Dr. Anderson, Dr. Thomas, Dr. Brown) and Orthopaedics and Rehabilitation (Dr. Marsh), University of Iowa, Iowa City, IA, the Department of Industrial and Manufacturing Systems Engineering, Iowa State University, Ames, IA (Dr. Frank), and the Department of Orthopaedic Surgery, University of California, San Francisco, San Francisco, CA (Dr. Kim).

The studies by Dr. Anderson and coauthors were funded by grants from the NIH/ NIAMS (P50AR055533 and R21AR054015), by a Medical Research Initiative Grant from the Roy J. Carver Charitable Trust at the University of Iowa, and by State of Iowa Economic Development appropriations to the Board of Regents under the Grow Iowa Values Fund.

Dr. Anderson has stock or stock options held in FxRedux. Dr. Thomas has stock or stock options held in FxRedux. Dr. Frank has stock or stock options held in FxRedux. Dr. Marsh or an immediate family member has received royalties from Biomet; has stock or stock options held in FxRedux; and serves as a board member, owner, officer, or committee member of the American Board of Orthopaedic Surgery, American Orthopaedic Association, and Orthopaedic Trauma Association. Dr. Brown or an immediate family member has stock or stock options held in FxRedux and serves as a paid consultant to Smith & Nephew. Dr. Kim or an immediate family member serves as a board member, owner, officer, or committee member of the Orthopaedic Research Society.

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Assessing and Minimizing the Adverse Mechanical Consequences of Articular Fractures To Decrease the Risk of Posttraumatic Osteoarthritis

Posttraumatic osteoarthritis (OA) occurs following a variety of joint injuries,1 but it is most common and predictable following articular fractures.2 The societal cost of posttraumatic OA is high (approximately $12 billion per year in the United States3) because pain and loss of function frequently lead to lost work capacity. In the armed services, posttraumatic OA following an articular fracture is now recognized as the leading cause of failure to return to active duty after injury.4

Apart from repairing the fracture, there has been little that can be done for the acute joint injury resulting from the trauma. However, recent research indicates that acuteimpact joint injuries initiate a cascade of biologic events leading to posttraumatic OA, and there is considerable evidence that new biologic interventions applied to the joint acutely could mitigate or arrest these adverse events5,6 (also see "Supplemental Biologic Intervention in the Management of Joint Injuries," below). These studies offer hope for a paradigm shift in the acute management of articular fractures; controlled clinical trials are needed to assess new interventions and prove their effectiveness.

Patients with articular fractures are in many ways ideal candidates for clinical trials of new therapies to treat joint injuries; the injury is identified and treated acutely, OA occurs relatively quickly and frequently, the arthritic changes are readily imaged using standard radiography, and standardized patientreported measures of pain and function are well established. However, articular fractures are complex injuries with substantial mechanical confounders (eg, injury severity, articular reduction quality) to a clinical trial of new biologic interventions. Recent research by our group has produced objective CTbased methods for measuring the severity of articular fractures and the cumulative articular surface contact stress caused by posttraumatic joint incongruity.7 The research has established that these measures could be used to identify patients who, despite the best current treatment, develop OA within 2 years of injury. The methods have since been expedited and can now be calculated quickly and efficiently, making it possible to perform multicenter clinical trials of new articular fracture treatments with patients stratified according to their underlying pathomechanical risk of posttraumatic OA.

Tibial pilon fracture patients are the ideal candidates for initial clinical trials because posttraumatic OA occurs within 2 years in 50% of patients,8 and the risk of ankle OA in the absence of trauma is low. However, because these fractures occur infrequently, they are not amenable to single-center clinical trials. Our group is partnering with the federally funded Major Extremity Trauma Research Consortium (METRC), a collaboration of 23 core civilian trauma centers, 4 military treatment facilities, and 38 satellite centers throughout the United States, which offers the opportunity to enroll a sufficient number of patients with these relatively unusual injuries for a clinical trial. This multicenter collaboration provides a strong platform for future trials of interventions to prevent posttraumatic OA.

Nevertheless, knowledge of these pathomechanical factors and their contribution to posttraumatic OA risk does little to help surgeons in their efforts to reduce and stabilize articular fractures to minimize posttreatment contact stress. The surgeon reconstructing a comminuted fracture essentially confronts a complex three-dimensional (3D) puzzle, with only a preoperative CT scan to aid in precisely determining the degree of comminution and individually localizing each fracture fragment. Accurate and precise preoperative planning, building on modern medical imaging and knowledge of the prefracture anatomy, can provide information instrumental for performing less invasive articular fracture surgery.

This observation led our group to study the potential of a new computational 3D puzzle-solving approach for analysis of articular fractures9 and then to develop a method of planning fracture reduction to optimize repositioning of displaced fracture fragments. Specialty imageanalysis tools were used to obtain fracture fragment geometries from CT data. The original anatomy was then restored by computationally matching fragment native bone surfaces to an intact template. These virtual reconstruction methods yielded average alignment errors of 0.39 mm in a series of 10 cases of tibial pilon fracture. In addition to precise fracture-reduction planning, preoperative 3D puzzle solutions identified potential articular deformities and structural bone loss that would persist after reduction because of comminution of fracture fragments. The 3D puzzle-solving algorithms have been incorporated into computer software (FxRedux, developed by us at the University of Iowa, Iowa City, IA, working with collaborators at the University of North Carolina at Charlotte) (Figure 1) for preoperative surgical reduction planning to manage complex multifragment articular fractures.

Figure 1

Figure 1

The ability of 3D puzzle solving to identify bone defects that cannot be reconstructed by fragment reduction (because of severe comminution of bone fragments) led the group to develop a method to identify regions where native bone would be "missing" after re-apposing the major fragments of a comminuted fracture bed. Although identifying "missing" bone regions is itself a novel and previously unanticipated outgrowth of the 3D puzzle-solving work, a second new and unique enabling technology offers additional benefit. This is the capability to automatically and rapidly manufacture complex physical shapes in immediately loadcapable implant materials, up to and including allograft bone, working directly from CT scan data.10,11

This is a potentially attractive alternative to the current options of working either with hand-shaped bone grafts or with prefabricated simple synthetic implant geometries, neither of which interdigitate intimately with the remaining bone. Bone allografts that precisely match the shape of osseous defects can be produced through subtractive rapid manufacturing, implemented via computer numerically controlled (CNC) machining by using unique technology developed at Iowa State University.11 Conventional additive rapid manufacturing techniques build up an object of interest layer by layer, via computer-controlled twodimensional patterns of fusion of stock material (typically powders, usually fused by lasers). In subtractive rapid manufacturing, by contrast, the shape of interest is physically machined from a preexisting contiguous solid object, similar in principle to processes currently in routine use in bone banks, where milling machines are used to prepare allograft implants from donor bones. In preliminary bench tests using a distal femur preparation from a sheep cadaver, stability differentials for several alternative constructs for segmental bone defect stabilization were measured and compared with standard-of-care methods; an anatomically shape-fitted defect filler provided nearly a fourfold improvement in construct stiffness.

Taken together, these developments, aimed at assessing and minimizing the adverse mechanical consequences of articular fractures, hold great promise for decreasing the presently unacceptably high risk of posttraumatic OA following articular fracture.

Donald D. Anderson, PhD Thaddeus P. Thomas, PhD Matthew C. Frank, PhD J. Lawrence Marsh, MD Thomas D. Brown, PhD

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Supplemental Biologic Intervention in the Management of Joint Injuries

In spite of the use of sophisticated and refined surgical techniques, posttraumatic osteoarthritis (OA) remains an unsolved clinical challenge. At least 12% of patients with lower extremity OA have a history of joint trauma, and 40% of patients with significant joint injuries go on to develop posttraumatic OA.12 Future approaches to improving patient outcomes will likely depend on more direct manipulation of the biologic responses to joint trauma. At the recent American Orthopaedic Society for Sports Medicine-National Institutes of Health U13 Post-joint Injury Osteoarthritis Conference II, the Early Arthritis Therapy (EARTH) study group established a road map to identify and evaluate intervention strategies following anterior cruciate ligament tears and other joint injuries, with the ultimate goal being to prevent or delay the onset of posttraumatic OA.

Acute cartilage damage at the time of injury initiates a cascade of events leading to secondary injury within the zone of injury. This zone of injury can expand beyond its initial borders in a manner analogous to myocardial infarction or stroke. Given the poor intrinsic capacity for cartilage healing, blocking this response may be a fruitful therapeutic approach. Recent experimental studies have identified some of the key players in this cascade, which may provide potential targets for intervention as well as candidate therapeutics with impressive in vitro and/or in vivo effects.

Reactive oxygen species (ROS) such as nitric oxide, superoxide, and peroxides are well-established contributors to cell death in a variety of tissue-injury models, including carti lage damage.13 A series of recent papers from the University of Iowa has clarified the contribution of ROS to chondrocyte death following mechanical injury and identified a potential candidate for drug intervention. In the first of these papers, the authors used a bovine osteochondral explant model to test the effects of the antioxidant N-acetylcysteine on chondrocyte survival after an impact of 7 J/cm2,6 The rescue effect was substantial, with viability increasing to 72% at 2 days postinjury compared with 40% in controls. Treatment could be delayed at least 4 hours postinjury and still provide substantial benefit. A subsequent paper provided evidence that the effects of ROS are likely mediated by activation of p38 mitogen-activated protein kinase and extracellular signalregulated protein kinase (ERK) 1 and 2, which then activate matrixdegrading enzymes.14 As anticipated, N-acetylcysteine treatment also enhanced proteoglycan content in the affected cartilage specimens measured 1 and 2 weeks postinjury. These findings provide substantial support for antioxidant treatment as a method to influence the development of postinjury OA.

Another promising candidate is the growth factor osteogenic protein-1/ bone morphogenetic protein-7 (OP-1/BMP-7), which currently has limited approval for clinical use as an enhancer of bone repair. A growing body of evidence suggests that OP-1/ BMP-7 may actually prove to be even more effective in the area of cartilage repair and cartilage protection. OP-1/BMP-7 has been shown to have both anabolic and anticatabolic effects on cartilage, and a recent study has shown striking effects on postinjury cartilage degeneration in vivo.5 The investigators used a sheep model of knee cartilage impact injury (30-MPa force) to test the effects of intra-articular injection of BMP-7 (340 μg) with a collagen particle carrier. Three different test groups received an initial drug injection on day zero, 21, or 90 after injury, with a second injection performed 1 week after the first. Animals were killed 90 days after the second injection. Animals that had received immediate treatment had only minimal evidence of cartilage degeneration at both the gross and microscopic levels, including analyses for apoptosis. In contrast, animals that had received treatment starting 90 days after injury did not benefit from OP-1/BMP-7, and animals that had received treatment starting 21 days after injury exhibited an intermediate result. The results were particularly striking given the limited bioavailability of the injected drug, which was detectible in the joint fluid by enzyme-linked immunosorbent assay only up to 72 hours postinjection.

Taken together, these studies, along with several related reports, provide strong evidence for biologic intervention supplemental to surgery in the management of joint injuries. Clinical trials have been proposed, and likely some promising candidates will be tested. Key questions that remain to be answered include which drug or drugs to test, when and how long to treat, what type or types of joint injuries would be most appropriate to treat, and how best to measure efficacy.

Hubert Kim, MD, PhD

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1. Buckwalter J: Mechanical injuries of articular cartilage, in Finerman G, ed: Biology and Biomechanics of the Traumatized Synovial Joint, The Knee as a Model. Rosemont, IL, American Academy of Orthopaedic Surgeons, 1992, pp 83-96.
2. Marsh JL, Buckwalter J, Gelberman R, et al: Articular fractures: Does an anatomic reduction really change the result J Bone Joint Surg Am 2002;84-A(7):1259-1271.
3. Brown TD, Johnston RC, Saltzman CL, Marsh JL, Buckwalter JA: Posttraumatic osteoarthritis: A first estimate of incidence, prevalence, and burden of disease. J Orthop Trauma 2006;20(10): 739-744.
4. Cross JD, Ficke JR, Hsu JR, Masini BD, Wenke JC: Battlefield orthopaedic injuries cause the majority of long-term disabilities. J Am Acad Orthop Surg 2011;19(suppl 1):S1-S7.
5. Hurtig M, Chubinskaya S, Dickey J, Rueger D: BMP-7 protects against progression of cartilage degeneration after impact injury. J Orthop Res 2009; 27(5):602-611.
6. Martin JA, McCabe D, Walter M, Buckwalter JA, McKinley TO: N-acetylcysteine inhibits post-impact chondrocyte death in osteochondral explants. J Bone Joint Surg Am 2009; 91(8):1890-1897.
7. Anderson DD, Marsh JL, Brown TD: OREF 2011 Clinical Research Award: The pathomechanical etiology of posttraumatic osteoarthritis following intraarticular fractures. Iowa Orthop J 2011; 31:1-20.
8. Marsh JL, Weigel DP, Dirschl DR: Tibial plafond fractures: How do these ankles function over time J Bone Joint Surg Am 2003;85(2):287-295.
9. Thomas TP, Anderson DD, Willis AR, Liu P, Marsh JL, Brown TD: ASB Clinical Biomechanics Award Paper 2010 Virtual pre-operative reconstruction planning for comminuted articular fractures. Clin Biomech (Bristol, Avon) 2011;26(2):109-115.
10. Anderson DD, Frank MC, McKinley TO, Brown TD: Fragment substitutes for anatomically-interfaced segmental bone defect repair. Presented at the 54th Annual Meeting of the Orthopaedic Research Society, San Francisco, CA, March 2-5, 2008.
11. Frank MC, Hunt CV, Anderson DD, McKinley TO, Brown TD: Rapid manufacturing in biomedical materials: Using subtractive rapid prototyping for bone replacement, in Proceedings of the Nineteenth Solid Freeform Fabrication Symposium. Austin, TX, Laboratory for Freeform Fabrication, University of Texas at Austin, August 2008. Available at: Accessed August 31, 2011.
12. Brown TD, Johnston RC, Saltzman CL, Marsh JL, Buckwalter JA: Posttraumatic osteoarthritis: A first estimate of incidence, prevalence, and burden of disease. J Orthop Trauma 2006;20(10): 739-744.
13. Kurz B, Lemke A, Kehn M, et al: Influence of tissue maturation and antioxidants on the apoptotic response of articular cartilage after injurious compression. Arthritis Rheum 2004; 50(1):123-130.
14. Ding L, Heying E, Nicholson N, et al: Mechanical impact induces cartilage degradation via mitogen activated protein kinases. Osteoarthritis Cartilage 2010;18(11):1509-1517.
© 2011 by American Academy of Orthopaedic Surgeons