How will patients with anterior cruciate ligament deficient knees be treated in the twenty-first century and beyond? No one, of course, can predict the future, but given the current state of knowledge of the anterior cruciate ligament injured knee, it may be possible to outline potential developments that can have an impact on the future practice of orthopaedic surgery.
The anterior cruciate ligament injured knee is an intriguing archetype of a significantly damaged musculoskeletal joint system. Although restoring function to an anterior cruciate ligament deficient knee may seem a straightforward structural and biomechanical problem, in reality, achieving full restoration of such a complex biologic system is vast.
The knee is a complex system which functions as a type of biologic transmission, accepting, transferring, and dissipating loads between the long lever arms of the femur and tibia.9 In this analogy, the ligaments represent nonrigid, adaptive linkages, and the cartilages, bearings within the transmission. The muscles represent both living engines (in concentric contraction) as well as brakes and dampening systems (in eccentric contraction). The multiple asymmetric components of the knee are extremely ancient in origin. The basic design of the tetrapod knee is so profoundly adapted to its load transference function that the morphology has changed little in the past 300 million years.10 There also has been an associated evolution of molecular and cellular mechanisms over eons to provide constant renewal and maintenance of tissues, as well as repair of damaged structures, with the purpose of preserving tissue homeostasis despite exposure to often high mechanical loads.
A knee that has been loaded with sufficient force to structurally fail the anterior cruciate ligament has sustained a significant perturbation of the system. Often such an injury results in a mosaic of associated tissue pathology including torn menisci,37,45 bone contusions,25 related ligament damage,30,31,38 and other less easily documented damage, such as injury of the proprioceptive sensor mechanisms.4,22 Tissue damage initiates extremely complex mechanisms of molecular and cellular repair, the details of which are only now beginning to be discovered. Furthermore, various tissues heal at different rates. Some tissues, such as extraarticular ligaments (medial collateral ligament)28 may heal rather rapidly given the appropriate biologic environment, whereas other structures, such as the intraarticular ligaments, may not heal at all.3,8 The intraarticular environment of the knee can be particularly harsh, both mechanically and biochemically, on structurally damaged ligaments and cartilage.1 From an evolutionary perspective, the presence of enzymatic processes designed to dissolve exposed intraarticular collagen makes sense: these biochemical processes minimize the possibility of loose tissue impingement.
Surgery represents a significant supraphysiologic stress of an already injured system.13 Thus, a knee that undergoes anterior cruciate ligament reconstruction must have been exposed to at least 2 major perturbing events. Full clinical recovery of knee function, if it occurs following anterior cruciate ligament reconstructive surgery, is a phenomenon that to a great extent relies on the patient's genetically controlled mechanisms of molecular and cellular healing, as much as to the specific surgery.
The functional capacity of a joint can be defined by the range of loads that can be accepted, transferred, and dissipated without inducing either supraphysiologic overload or structural failure. A method of graphically representing this capacity with increasing loads applied on the vertical axis, and frequency of loading on the horizontal axis, is termed the envelope of function9(Fig 1). The area within the curve represents a zone of homeostatic loading for a given knee in a given period. The responsibility of orthopaedic surgeons is to maximize this envelope of function for each joint as predictably and safely as possible. An injured joint's own unique anatomic, kinematic, physiologic, and treatment factors determine its envelope of function, or zone of homeostatic loading. Future advances in treatment of anterior cruciate ligament deficient knees will come from therapeutic improvements in the areas of anatomy, kinematics, and physiology. Before presenting possible future therapeutic directions for the anterior cruciate ligament deficient knee, it would be appropriate to consider the current status of these 3 areas.
Despite recent efforts to recreate the anatomic structure of the anterior cruciate ligament by various surgical techniques, normal morphology is not being restored. The broad asymmetrical femoral and tibial footprints of the anterior cruciate ligament origin and insertion are not being recreated. Most current reconstructions still are substituting a cord or cords for the complex fan morphology of a normal undamaged anterior cruciate ligament. To some degree the anteromedial bundle of the anterior cruciate ligament is being reconstructed.
The microanatomy of the anterior cruciate ligament is complex and composed of fascicles within which are subfascicular units containing fibers and fibrils11(Fig 2). Recent research using electron microscopy shows that the normal pattern of mixed large and small fibrils is not being achieved in current anterior cruciate ligament reconstructive techniques29,32,39,41(Fig 3). The insertion of the normal anterior cruciate ligament into bone occurs through complex transition zones of fibrocartilage and calcified cartilage2(Fig 4). These normal transition zones have not been recreated by current techniques.
Neurologic elements have been well documented in normal anterior cruciate ligaments36(Fig 5). These neurologic systems probably serve an important sensory/proprioceptive function in normal anterior cruciate ligaments.19,21,22 Restoration of normal neural element morphology and distribution has not been documented in current human anterior cruciate ligament reconstructions.
The biomechanical integrity of current anterior cruciate ligament reconstructions in humans is unknown. The fact that many postoperative knees manifest increased structural laxity implies that the strength of such reconstructions was insufficient for the postoperative applied load. Unfortunately, no animal model has shown restoration of normal anatomic or biomechanical characteristics of a reconstructed anterior cruciate ligament. Even excellent appearing anterior cruciate ligament reconstructions have been shown to fail at relatively low loads.18,43
Cyril Frank, MD, of Calgary, Alberta, who along with his coworkers,6,7,15,16,44 has approached the problem of restoring function in ligament damaged knees, chose the medial collateral ligament in a lapine model for its relative simplicity, before investigating the anterior cruciate ligament injured knee. Despite extensive research, full restoration of anatomy, biomechanics, kinematics, and tissue homeostasis has not been achieved following controlled injuries of the medial collateral ligament. Considering the experience of his research team with this less complex ligament injury model, full restoration of human anterior cruciate ligament injured knees must therefore be considered even more difficult to achieve.
Restoration of normal recruitment patterns of anterior cruciate ligament fibers under load has not been shown in anterior cruciate ligament reconstructed knees. The functional kinematics of a given joint are due in large part to complex neuromuscular mechanisms involving proprioception and cerebellar sequencing of motor unit contractions.26,34,35 Recent work by Barrack et al,4 and Wojtys and Huston46 shows a significant difference between the proprioception of a normal knee and an anterior cruciate ligament deficient knee. Restoration of normal proprioceptive function has not been shown with current reconstructive techniques. Barrett,5 however, has shown a close correlation between knee proprioception and the functional outcome following anterior cruciate ligament reconstruction.
The physiologic capability of all components of a living knee to maintain tissue homeostasis is vital for normal long term function. At present, only the metabolic characteristics of the osseous tissues are visualized easily (with scintigraphic techniques).12 No similar physiologic imaging capability presently exists for soft tissues. Restoration of osseous homeostasis in anterior cruciate ligament reconstructed knees has been documented using current surgical techniques.11,12 Few treatment options exist to control or enhance an individual's molecular and cellular maintenance and reparative mechanisms.
PRINCIPLES OF TREATMENT
There are several basic principles that should guide future treatment for anterior cruciate ligament deficient knees. Whatever graft or component that is implanted or induced to form should ultimately result in a structure that is comprised of the patient's own living cells. This living system must be capable of homeostatic self repair with normal loading activities. Reconstructions of the anterior cruciate ligament linkage should be in the proper orientation, inserting into the normal footprint areas with normal structural and biomechanical integrity.
Normal microanatomic characteristics such as the appropriate mix of large and small fibril patterns, normal crimp patterns, transition zones, and ideally normal neural elements should be restored. There should be a normal pattern of recruitment of the anterior cruciate ligament fibers under load that, in combination with proper neuromuscular function, results in normal derived kinematics. Whatever techniques are developed should be affordable for the average patient.
FUTURE TREATMENT OF THE ANTERIOR CRUCIATE LIGAMENT DEFICIENT KNEE
Short of startling advances in physics and biophysics resulting in the capability to manipulate and transport matter, rapidly forming in vivo, a living anterior cruciate ligament, the future solutions seem likely to be purely in the biologic realm. Looking to possible future biologic developments relative to treating anterior cruciate ligament deficient knees, there are roughly 3 stages of technical maturity, corresponding in time to the distant future, midterm future, and near future. Because the timing of advances in any scientific field are difficult to predict, one hesitates to define too narrowly when these stages of technical maturity will occur. However, the author visualizes the near future as being by the end of the twentieth century, the midterm future occurring during the early twenty-first century, and the distant future occurring in the midtwenty-first century or beyond.
Distant Future: Ultimate Goal, Full Restoration
The ultimate goal for treating anterior cruciate ligament deficient knees is full restoration of all knee components and subsystems to the preinjury status. This would include full restoration of the macroanatomy and microanatomy of the anterior cruciate ligament, and of all the kinematic, neuromuscular, and physiologic factors extant in a normal living knee. To achieve this status will require far advanced biologic and genetic capabilities that have not yet been developed or demonstrated. A thorough understanding of the human genome and the biologic effects of the various alleles should allow restoration of all subsystems including the neurologic components.
Induction of molecular and cellular mechanisms, currently only active in humans during prenatal developmental stages, may be necessary for full restoration of tissues. It is known that certain members of a group of amphibians, the Urodela, (salamanders and newts) can regenerate whole limbs in mature animals following major trauma.14,24,27,42 Perhaps such a potential physiologic capability exists, or can be induced, in humans that could result in full restoration of all knee systems. Full restoration of proprioceptive, cerebral, cerebellar, spinal reflex, and motor unit control mechanisms also would need to be accomplished.
It is difficult to foresee what role traditional surgery may have in such a technologically advanced era. It is suspected that surgical guidance and placement of biologically induced structures will be required, although actual control of the process may be done remotely through dynamically actuated mechanisms resembling a computer keyboard. Certainly surgery as it is known today, will seem rudimentary. With advanced genetic control of biologic processes, restoration of normal dermal elements also may be possible, allowing for truly scarless surgery.
Midterm Future: Achievable Goals, Restoration of the Anterior Cruciate Ligament Deficient Knee Without Traditional Autograft
Full restoration of anterior cruciate ligament anatomy, including the possible restoration of neurologic elements without the need for the traditional detrimental macroharvesting of the patient's own tissues, is a goal that seems foreseeable biotechnologically. An ideal graft source would be one that is a temporary stent that could be resorbed and replaced, eventually reconstituting the patient's own morphologically and structurally normal anterior cruciate ligament. Such a stent ideally would be capable of inducing normal morphologic and biomechanical characteristics, such as transition zones. Although straightforward in concept, such a graft probably will be exceedingly difficult to achieve in actuality. The biologic processes of resorbing the temporary stent structure are not necessarily coupled to the processes of forming anatomically and structurally normal anterior cruciate ligament fascicles. Controlling the rate of resorption to match the rate of fibroblast restoration in such a graft may prove to be a daunting challenge. Sufficient genetic variations may exist in the patient population necessitating different biologic substrates for such a resorbable graft, according to the different physiologic characteristics of an individual patient. One can foresee genetic testing of patients determining various phenotypical groupings that could be used in deciding which biologic substrate would be best for an individual patient, (fast graft resorbers, versus slow graft resorbers). It is possible that such a replaceable stent could be infused with the patient's own genetic material before implantation.
It is conceivable that we will learn to manipulate the local physiologic environment with additives such as various tissue growth factors including nerve growth factors, to induce more normal restoration of microanatomy and neurologic components.20 A strong caveat should be observed with any such approach using new and powerful biologic and genetic techniques. Such techniques could have unforeseen consequences.17 A stent preloaded with substances such as tissue growth factors could conceivably induce pathologic neoplasms and painful hypersensitive neuromas, violating the Hippocratic dictum of primum non nocere.23 The successful development of such a graft would require extensive basic science and clinical testing to assure, not only efficacy, but safety.
It also seems possible that an appropriate mammalian model could be induced, theoretically, to grow human genetically coded structures. Such grafts would be genetically equivalent to allografts, but with uniform and predictable characteristics, and minimal risk of microbial transmission. It also seems possible that in the midterm future, techniques may be developed that could grow the patient's own cells in vitro, recreating an implantable anterior cruciate ligament structure.
It is possible in the midterm future that a genetic transplant coding for the broad spectrum of molecular and cellular healing properties and maintenance mechanisms may be developed. Individuals with robust molecular and cellular homeostatic and reparative mechanisms could be identified, and their appropriate genetic material decoded. Such genetic information could be incorporated into a patient, either systemically, or locally into a graft system, to induce improved healing properties.
It is possible that unsuspected biophysical properties will be discovered, such as the presence of soft tissue bioelectric fields equivalent to those demonstrated in bone, that may help orient fibers in ligaments and enhance their maturation.
Near Future: Practical Goals, Improvement of Current Techniques
In the near future, it would be beneficial to develop autografting techniques that are less damaging than current techniques. Currently, the author favors the clinical outcome following central third patellar tendon reconstruction, and has proven that osseous homeostasis is possible with this technique.12,13 However, there can be persistent sequelae with, for example, patellofemoral sensitivity in some patients. New techniques, such as use of the quadriceps tendon as a graft source, being developed by Stäubli,40 may represent an excellent autograft with minimal long term morbidity. Current trials with multiple looped hamstring tendons also may prove to be an effective graft source with low long term morbidity. Such grafts may have the advantage due to filling the bone tunnels, of attaching directly to the anterior cruciate ligament insertion sites.
Allografts can be improved in safety, reliability, and control of the immune system response. Techniques must be developed to eradicate all viable microbes from such tissue sources without substantially weakening the graft. Better fixation techniques need to be developed that, ideally, secure the graft at the anterior cruciate ligament insertion sites rather than deeper in the tunnels, and induce recreation of normal transition zones with minimal morbidity. Current work on resorbable interference fit screws represents initial work in this area. In the near future biodegradable bone cement may be developed that allows for immediate fixation of the graft, and eventual replacement with normal osseous tissue. Care must be taken with such a technique not to cause necrosis of the tissues by complete encapsulation, resulting in a cement sarcophagus. Factors that induce significant biologic system activation must be developed with caution so as not to result in untoward effects, such as necrosis of the graft, osteolysis, or loosening of the bonegraft interface.
New techniques to assist proper healing of acutely injured anterior cruciate ligaments, through, for example, control of the enzymatic and biologic environment seems possible, which in certain cases may obviate the need for reconstruction.
Regarding purely artificial grafts, the long term success with their use as a substitution for the anterior cruciate ligament in young, normally active, or athletically active individuals is not foreseen. Without the capacity for self repair, any substance, no matter how strong initially, will ultimately fail given sufficient repetitive loading. There is no potential for nerve sensor restoration. Other problems exist with artificial grafts, such as potential for tunnel drift, and osteolysis secondary to wear particles that also may not be easily solved. Purely artificial grafts may have some limited role in low demand knees.
Future advances in technical aspects of surgery such as 3-dimensional arthroscopic imaging and robotic surgery may assist in better visualization and placement of graft position.
There are multiple ancillary biologic system improvements that also can play a role in the treatment and management of anterior cruciate ligament deficient knees. In particular, the factors that initiate, sustain, and resolve related soft tissue problems, such as muscle atrophy, need to be discovered and ultimately controlled. Improvements in rehabilitation that enhance the cerebellar-proprioceptive control of muscle unit sequencing and improvements in bracing techniques can result in better treatment of anterior cruciate ligament injured knees.
Better methods of assessing and tracking collateral damage of all tissues need to be developed in addition to the anterior cruciate ligament in such injured knee systems. Reliable indicators of soft tissue homeostasis need to be developed. Positron emission tomography, or a related imaging technology, has the potential to play that role in the future. Perhaps some day orthopaedists will be able to view a transparent 3-dimensional hologram of a knee with the differential degree of healing of various tissues, including the cruciate ligaments, menisci, and bone, represented by various colors and intensities.
When speculating about the future, one must always recognize the possibility of unexpected technological breakthroughs that may provide profound advancements. Such advances, if they occur, are likely to be in the biologic realm, but perhaps even currently unrelated technologies may play a role, for example, nanotechnology, that involves the use of microscopic machines to build or shape structures molecule by molecule.33 Advancements in the management of complex biologic system damage, such as an anterior cruciate ligament injured knee, will no doubt occur through multiple sources and vectors. Surgical implantation of grafts will remain an important part of a rational comprehensive treatment program, designed to maximize the function of anterior cruciate ligament injured knees, well into the foreseeable future.
Techniques designed to work symbiotically with the patient's own evolutionarily honed biologic factors will be a hallmark of successful orthopaedic treatment. The basic principle, no matter what techniques are developed, should be to achieve the greatest functional range of load acceptance and transference with the least degree of risk for the patient.
The author thanks the following individuals for their help and guidance in the preparation of this work: Geoffrey Vaupel, MD, William Berger, MD, Ann Dye, RN, Lottie Applewhite, Anne Shew, and Rebecca Larsen.
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