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Surface Treatment of Flexor Tendon Autografts with Carbodiimide-Derivatized Hyaluronic AcidAn in Vivo Canine Model
Chunfeng Zhao, MD1; Yu-Long Sun, PhD1; Peter C. Amadio, MD1; Toshikazu Tanaka, MD1; Anke M. Ettema, MD1; Kai-Nan An, PhD1
1 Biomechanics Laboratory, Division of Orthopedic Research, Mayo Clinic College of Medicine, 200 First Street S.W., Rochester, MN 55905. E-mail address for C. Zhao: zhaoc@mayo.edu
View Disclosures and Other Information
In support of their research for or preparation of this manuscript, one or more of the authors received grants or outside funding from the Orthopaedic Research and Education Foundation. None of the authors received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.
Investigation performed at the Biomechanics Laboratory, Division of Orthopedic Research, Mayo Clinic College of Medicine, Rochester, Minnesota

The Journal of Bone and Joint Surgery, Incorporated
J Bone Joint Surg Am, 2006 Oct 01;88(10):2181-2191. doi: 10.2106/JBJS.E.00871
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Background: Clinical and experimental studies have demonstrated that restrictive adhesions and poor digital motion are common complications after extrasynovial tendon grafting in an intrasynovial environment. The purpose of this study was to test the hypothesis that surface modification of an extrasynovial tendon with use of a carbodiimide-derivatized hyaluronic acid-gelatin polymer (cd-HA) improves gliding ability and digital function after tendon grafting in a canine model in vivo.

Methods: The peroneus longus tendons from both hindpaws of twenty-four dogs were harvested and transplanted to replace the flexor digitorum profundus tendons in the second and fifth digits of one forepaw. Prior to grafting, one of the peroneus longus tendons was coated with cd-HA, which consists of 1% hyaluronic acid, 10% gelatin, 0.25% 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC), and 0.25% N-hydroxysuccinimide (NHS), while the other was immersed in saline solution only. Eight dogs were killed at one, three, and six weeks. Digital normalized work of flexion, tendon gliding resistance, and hyaluronic acid quantification (with the hyaluronic acid-binding-protein staining technique) were the outcome measures.

Results: The normalized work of flexion of the tendons treated with cd-HA was significantly lower than that of the saline-solution-treated controls at each time-point (p < 0.05). The gliding resistance of the cd-HA group was significantly lower than that of the saline-solution group at three and six weeks (p < 0.05). The ratio between the intensity of staining of the cd-HA-treated tendons with that of the saline-solution-treated controls was significantly greater at time-0 than at three or six weeks (p < 0.05), but there was no significant difference between time-0 and one-week values.

Conclusions: Treating the surface of an extrasynovial tendon autograft with a carbodiimide-derivatized hyaluronic acid-gelatin polymer decreases digital work of flexion and tendon gliding resistance in this flexor tendon graft model in vivo.

Clinical Relevance: cd-HA gelatin may provide surgeons with a new and useful method to improve the quality of tendon graft surgery.

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    Henry Hamilton, FRCS(C)
    Posted on November 07, 2006
    A Brief History Of Studies Concerning The Mechanism of Joint Lubrication
    The Port Arthur Health Centre, Thunder Bay, Ontario, CANADA

    To The Editor:

    A patient with a Judet arthroplasty (acrylic hemiarthroplasty introduced by the Judet brothers of Paris in 1946) that emitted an audible squeak sparked John Charnley’s interest in joint lubrication(1). In 1936, E. Shirley Jones, a British general practitioner, had conducted experiments in which he used an amputated finger to act as the pivot of a pendulum(2). It will be recalled that a grandfather clock keeps good time because the duration of the swing is constant, whether the amplitude is large or small. Jones noted an exponential decay in the amplitude of the swing, indicating that the frictional resistance was disproportionately high at high speeds of sliding. This was consistent with a viscous lubricant, and supported a hydrodynamic mechanism of lubrication. Hydrodynamic lubrication works well in engine bearings, where there is a contained lubricant, and continuous high-speed rotation. The rotating shaft drives a wedge of lubricant that can support a heavy load. When the rotation stops, the lubricant is no longer able to support the load. Charnley was concerned that in synovial joints, where the movement is slow, intermittent and oscillating, and where “stick” does not occur, hydrodynamic lubrication was improbable. He repeated Jones’ experiments with an ankle joint. Because of this joint’s inherent stability, the ligaments could be stripped. There was now a straight-line decay in the swing amplitude. Charnley realised that the exponential decay observed by Jones was due to the collateral ligaments that caused a greater resistance at large than at small amplitudes of swing. The straight-line decay of the ankle joint indicated that as the speed of sliding slowed, the coefficient of friction remained constant. This is characteristic of boundary lubrication. It was on the basis of this research, that Charnley experimented with polytetrafluorethylene bearings, which failed, and in November 1962, introduced the low friction arthroplasty (polyethylene on stainless steel), which succeeded.

    In the 1980's mechanical engineers still believed that boundary lubrication was not compatible with the very low coefficients of friction found in synovial joints. They continued to advance complex models to explain effortless sliding on fluid films.

    Brian Hills, a Brisbane paediatric respirologist, with a Cambridge degree in physical chemistry, took a new approach. He proposed that surfactants, and in particular surface-active phospolipids, bonded electrostatically to mesothelial surfaces, and were the universal lubricating system in the body. Surfactants allow the eyeball to rotate in the orbit, the lungs to expand in the pleura, the heart to beat within the pericardium, the intestines to glide within the peritoneum, and synovial joints to move and tendons to slide(3,4,5,6,).

    In synovial joints, terminal quaternary ammonium cations bond to cartilage proteoglycan anions. This reversible bond orients the non-polar end of the surfactant molecules outward. These non-polar fatty acids throng to form a cohesive surface structure capable of bearing physiological loads. A droplet of saline placed on normal articular cartilage, which has been rinsed free of synovial fluid, has a contact angle of >90º, indicating hydrophobia(7). When the surfactant is removed, the cartilage becomes hydrophilic, and the drop of saline spreads over the surface. This surface-active phospholipid (SAPL), boundary lubricant allows: instantaneous movement or anti-stick; kinetic physiological coefficients of friction, and prevents wear.

    Brian Hills’ 24 years of elegant experiments and reports provide the first credible explanation of synovial joint lubrication. This concept raises many issues: We must re-draw the cross section of articular cartilage. In EM studies, aldehydes employed as fixatives destroyed the hydrophobic lipids. With tannic acid as a fixative, the surfactant coating is preserved. Synovial fluid has been considered as a lubricant, but if the synovial fluid is replaced by saline, the lubrication remains the same until the adsorbed surfactant is exhausted. As early as 1969, Little et al.(8) suggested that fats could play a role in joint lubrication. They showed that rinsing the joint with a lipid solvent increased the friction 150%. These experiments were confirmed by Hills & Thomas(9). Hyaluronic acid (HA) was believed to be a lubricant, and it is sometimes injected into joints for this purpose. But HA has no load bearing capability, and when removed by hyaluronidase, joint lubrication is unaffected. Lubricin was thought to act as a boundary lubricant, but is not adsorbed by the joint surface, and is hydrophilic. Any beneficial effects of HA or lubricin are due to surfactant contamination of these macromolecules(10).

    SAPLs are produced in the lamellar bodies of type B synoviocytes(11). The water-soluble macromolecules HA and lubricin transport the hydrophobic surfactant through the synovial fluid to the articular surface.

    Rabinowitz(12) showed that traumatised joints contain less phospholipid than non-traunatised joints. Hills & Monds(13) showed that surfactant was deficient in hips and knees undergoing arthroplasty. Together these studies suggest a relationship between trauma, loss of surfactant, and osteoarthritis. Vecchio et al.(14) showed that intra-articular injections of exogenous synthetic surfactant, dipalmitoyl phosphatidylcholine (DPPC) is helpful, providing sufficient cartilage is left to lubricate. Purbach et al.(15) showed that rinsings from prostheses removed during revisions contain surfactant, but it was often deficient. Bell et al.(16) have shown in the laboratory that the addition of surfactant to bovine serum albumin, used as a lubricant in simulated trials, reduced the wear rate of UHMWPE cups by 1-2 orders of magnitude. The surfactant lubrication of our natural, and artificial joints is the same, and deficiencies of surfactant may contribute to failure in both. Failure of our joints, like those of engine bearings, may be due to failure of the lubricating system.

    Hills' work has not received the recognition that it deserves, and even some of his countrymen appear to be unaware of how joints are lubricated. Back et al.(17), (Melbourne) reported “Early results of primary Birmingham hip resurfacings”, and noted that 3.9% of their patients experienced an episode of squeaking while the hip was under load. They attributed this “to disruption of the fluid film between the two bearing surfaces”.

    Harmonic vibrations or squeak occurs in an arthroplasty, under load, when a momentary cold weld or “stick”, is followed by release or “slip”. The orthopaedic community should be attentive to the squeak that was manufactured in Paris, heard in Manchester, explained in Brisbane, and misunderstood in Melbourne.

    The author(s) of this letter to the editor did not receive payment or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the author(s) are affiliated or associated.


    1. Charnley J. Low Friction Arthroplasty of the Hip. Theory and Practice. Springer-Verlag New York 1979; 1: 3-15.

    2. Jones ES. Joint lubrication. Lancet 1936; 1: 1043.

    3. Hills BA, Butler BD. Surfactants identified in synovial fluid and their ability to act as boundary lubricants. Annals Rheumat Dis. 1984:43:641-648.

    4. Hills BA. Oligolamellar nature of the articular surface. J Rheumatol. 1990:17: 349-355.

    5. Hills BA. Boundary lubrication in vivo. Proc Instn Mech Engrs 2000; 214H: 83-94.

    6. Hills BA, Crawford RW. Normal and prosthetic synovial joints are lubricated by surface-active phospholipid. A hypothesis. J. Arthroplasty 2003; 18, 4: 499-505.

    7. Hills BA. Synovial surfactant and the hydrophobic articular surface. J Rheumatol. 1996; 23 (Editorial):1323-5.

    8. Little T, Freeman MAR, Swanson SAV. Experiments on friction in the human hip joint. Lubrication and wear in joints (Ed. Wright V) 1969 (Sector, London): 110-116.

    9. Hills BA, Thomas K. Joint stiffness and ‘articular gelling’: inhibition of the fusion of articular surfaces by surfactant. Br J Rheumatol. 1998; 37: 532-538.

    10. Hills BA, Monds MK. Enzymatic identification of the load-bearing boundary lubricant in the joint. Br J Rheumatol. 1998; 37:137-142.

    11. Schwarz IM, Hills BA. Synovial surfactant: lamellar bodies in type B synoviocytes and proteolipid in synovial fluid and the articular lining. Br J Rheumatol. 1969; 35:821-827.

    12. Rabinowitz JL, Gregg JR, Nixon JE. Lipid composition of the tissues of human knee joints. II Synovial fluid in trauma. Clin Orthop Relat Res. 1984; 190: 292-298.

    13. Hills BA, Monds MK. Deficiency of lubricating surfactant lining the articular surfaces of replaced hips and knees. Br J Rheumatol. 1998; 37: 143-147.

    14. Vecchio P, Thomas R, Hills BA. Surfactant treatment for osteoarthritis. Rheumatology (letter) 1999: 1020-1021.

    15. Purbach B, Hills BA, Wroblewski BM. Surface-active phospholipid in total hip arthroplasty. Clin Orthop Relat Res. 2002; 396: 115-8.

    16. Bell J, Tipper JL, Ingham E, et al. Influence of phospholipid concentration in protein-containing lubricants on the wear of UHMWPE in artificial hip joints. Proc Inst Mech Eng 2001; H215: 259.

    17. Back DL, Dalziel R, Young D, Shimmin A. Early results of primary Birmingham hip resurfacings. J Bone Joint Surg Br. 2005; 87: 324-329.

    Chunfeng Zhao, M.D.
    Posted on November 02, 2006
    Dr. Zhao and Colleagues Respond to Dr. Hamilton
    Mayo Clinic

    We thank Dr. Hamilton for his comments. While it is true that, in the normal joint, hyaluronic acid provides viscosity without significantly affecting the lubrication of articular cartilage(1), our model is rather different.

    First, this is a tendon, not a joint. It is not unlikely that tendon and articular cartilage have different lubrication mechanisms.

    Second, there is no evidence that our commercial source of hyaluronic acid is contaminated with phospholipid.

    Third, we have tested this surface treatment on tendons in vitro(2) in an environment with no exogenous phospholipid or other natural lubricants, such as lubricin (3), and noted a similar reduction in friction as observed in this in vivo study. Our data clearly show that friction is reduced when this surface treatment, which fixes hyaluronic acid to the tendon surface, is applied, both in vitro and in vivo.

    Fourth, other studies have shown that treatment of the surface of an intrasynovial tendon with hyaluronidase increases friction (4), again suggesting a role for surface bound hyaluronic acid on friction in tendons. Surely, if friction is reduced when hyaluronic acid is added to the system, and increased when hyaluronic acid is removed, it is logical to hypothesize that it is the hyaluronic acid, and not some possible phospholipid contaminant, that is the responsible agent. We do not deny that phospholipids, lubricin, and other matrix molecules play a role in tendon lubrication, either alone or in combination; indeed, we have recently reported on the presence of lubricin in tendons(5). We do strongly disagree, though, with the assertion that the synthetic fixation of hyaluronic acid to a tendon surface has no effect on friction, as multiple studies have, to the contrary, demonstrated such an effect (2,4,6 -8).

    Fifth, the assertion that it is not the hyaluronic acid but, instead, some interaction between hyaluronic acid and an undetected phospholipid associated with the hyaluronic acid that is responsible for the friction reduction is not testable in a biological system, where phospholipid “contamination” is ubiquitous in cell membranes. If a hypothesis cannot be disproved, it is not scientifically valid(9).

    Finally, we also strongly disagree with the assertion that hyaluronic acid is a biological glue. We are unaware of any data to support this assertion, and the presence of hyaluronic acid is well known to support cell proliferation and migration, not cell fixation(10-13). Indeed, our surface treatment also reduced adhesion formation, strong evidence against any role of hyaluronic acid as a glue.


    1. Hills BA, Monds MK. Enzymatic identification of the load-bearing boundary lubricant in the joint. British Journal of Rheumatology. 1998;37(2):137-42.

    2. Sun YL, Yang C, Amadio PC, Zhao C, Zobitz ME, An KN. Reducing friction by chemically modifying the surface of extrasynovial tendon grafts. J Orthop Res. 2004;22(5):984-9.

    3. Jay GD, Cha CJ. The effect of phospholipase digestion upon the boundary lubricating ability of synovial fluid.[comment]. Journal of Rheumatology. 1999;26(11):2454-7.

    4. Uchiyama S, Amadio PC, Ishikawa J, An KN. Boundary lubrication between the tendon and the pulley in the finger. J Bone Joint Surg (Am). 1997;79(2):213-8.

    5. Sun Y, Berger EJ, Zhao C, Jay GD, An KN, Amadio PC. Expression and mapping of lubricin in canine flexor tendon. J Orthop Res. 2006;24(9):1861 -8.

    6. Momose T, Amadio PC, Sun YL, Zhao C, Zobitz ME, Harrington JR, An KN. Surface modification of extrasynovial tendon by chemically modified hyaluronic acid coating. Journal of Biomedical Materials Research. 2002;59(2):219-24.

    7. Nishida J, Araki S, Akasaka T, Toba T, Shimamura T, Amadio PC, An KN. Effect of hyaluronic acid on the excursion resistance of tendon grafts. A biomechanical study in a canine model in vitro. J Bone Joint Surg (Br). 2004;86(6):918-24.

    8. Yang C, Amadio PC, Sun YL, Zhao C, Zobitz ME, An KN. Tendon surface modification by chemically modified HA coating after flexor digitorum profundus tendon repair. J Biomed Mater Res. 2004;68B(1):15-20.

    9. Popper K. Science as Falsification, in Theodore Schick, ed., Readings in the Philosophy of Science. Mayfield Publishing Company, Mountain View, CA. 2000: pp. 9-13.

    10. Amiel D, Ishizue K, Billings E, Wiig M, Berg JV, Akeson WH, Gelberman R. Hyaluronan in flexor tendon repair. J Hand Surg. 1989;14A:837-843.

    11. Wiig M, Abrahamsson SO, Lundborg G. Effects of hyaluronan on cell proliferation and collagen synthesis: a study of rabbit flexor tendons in vitro. J Hand Surg (Am). 1996;21(4):599-604.

    12. Burns JW, Skinner K, Colt MJ, Burgess L, Rose R, Diamond MP. A hyaluronate based gel for the prevention of postsurgical adhesions: evaluation in two animal species. Fertility & Sterility. 1996;66(5):814-21.

    13. Liu N. Metabolism of macromolecules in tissue. Lymphat res biol. 2003;1(1):67-70.

    Henry Hamilton, FRCS(C)
    Posted on October 30, 2006
    Hualuronic Acid Is Not A Joint Lubricant
    The Port Arthur Health Centre, Thunder Bay, Ontario, CANADA

    To The Editor:

    Chunfeng Zhao et al. article, "SURFACE TREATMENT OF FLEXOR TENDON AUTOGRAFTS WITH CARBODIIMIDE-DERIVATIZED HYALURONIC ACID"(1) is an ingenious study, but in it, they state that hyaluronic acid (HA) is a lubricant! I disagree.

    This macromolecule is more suitable for use as a glue than a lubricant. Elimination of HA from a joint with hyaluronidase has no effect on the coefficient of friction.

    HA does assist in the transfer of the boundary lubricant, surface active phospholipid (SAPL)(2)from the synovium to the articular or tendon surface. It is difficult to isolate HA uncontaminated by SAPL. This may be why this experiment worked.

    The author(s) of this letter to the editor did not receive payment or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the author(s) are affiliated or associated.


    1. Zhao C, Sun YL, Amadio PC, Tanada T, Ettema AM, An KN. Surface Treatment of flexor tendon autographs with carbodiimide-derivatized hyaluronic acid. J Bone Joint Surg Am. 2006;88:2181-91.

    2. Hills BA. Normal and prosthetic joints are lubricated by SAPL Journal Arthroplasty. 2003;18,4:499-505. (The references include many of Hills' papers over the last 24 years, which explain the universal human lubricating system).

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