Studies in Flexor Tendon Wound Healing: Neutralizing Antibody to TGF-β1 Increases Postoperative Range of Motion

Abstract

The postoperative outcome of hand flexor tendon repair remains limited by tendon adhesions that prevent normal range of motion. Recent studies using in situ hybridization techniques have implicated transforming growth factor beta-1 (TGF-beta1) in both intrinsic and extrinsic mechanisms of repair. TGF-beta1 is a growth factor that plays multiple roles in wound healing and has also been implicated in the pathogenesis of excessive scar formation. The purpose of this study was to examine the effect of neutralizing antibody to TGF-beta1 in a rabbit zone II flexor tendon wound-healing model. Twenty-two adult New Zealand White rabbits underwent complete transection of the middle digit flexor digitorum profundus tendon in zone II. The tendons were immediately repaired and received intraoperative infiltration of one of the following substances: (1) control phosphate-buffered saline; (2) 50 microg neutralizing antibody to TGF-beta1; (3) 50 microg each of neutralizing antibody to TGF-beta1 and to TGF-beta2. Eight rabbits that had not been operated on underwent analysis for determination of normal flexion range of motion at their proximal and distal interphalangeal joints, using a 1.2-N axial load applied to the flexor digitorum profundus tendon. All rabbits that had been operated on were placed in casts for 8 weeks to allow maximal tendon adhesion and were then killed to determine their flexion range of motion. Statistical analysis was performed using the Student's unpaired t test. When a 1.2-N load was used on rabbit forepaws that had not been operated on, normal combined flexion range of motion at the proximal and distal interphalangeal joints was 93+/-6 degrees. Previous immobilization in casts did not reduce the range of motion in these forepaws (93+/-4 degrees). In the experimental groups, complete transection and repair of the flexor digitorum profundus tendon with infiltration of control phosphate-buffered saline solution resulted in significantly decreased range of motion between the proximal and distal phalanges [15+/-6 degrees (n = 8)]. However, in the tendon repairs infiltrated with neutralizing antibody to TGF-beta1, flexion range of motion increased to 32+/-9 degrees (n = 7; p = 0.002). Interestingly, a combination of neutralizing antibody to TGF-beta1 and that to TGF-beta2 did not improve postoperative range of motion [18+/-4 degrees (n = 7; p = 0.234)]. These data demonstrate that (1) the rabbit flexor tendon repair model is useful for quantifying tendon scar formation on the basis of degrees of flexion between proximal and distal phalanges; (2) intraoperative infiltration of neutralizing antibody to TGF-beta1 improves flexor tendon excursion; and (3) simultaneous infiltration of neutralizing antibody to TGF-beta2 nullifies this effect. Because TGF-beta1 is thought to contribute to the pathogenesis of excessive scar formation, the findings presented here suggest that intraoperative biochemical modulation of TGF-beta1 levels limits flexor tendon adhesion formation.

In vitro and in vivo effects of PDGF-BB delivery strategies on tendon healing: a review

“…Local delivery of TGFβ1 was shown to improve the biomechanical and histological properties of the tendons (Halper, 2014;Majewski et al, 2012). However, TGFβ1 is a growth factor associated with complex biological signalling and scar and adhesion formation (Chang et al, 2000b;Galatz et al, 2006;Penn et al, 2012). Exogenous delivery of FGF-2 in a canine model did not result in improved biomechanical or molecular properties of the treated tendons (Thomopoulos et al, 2010b), on the other hand FGF-2 gene transfer has yielded more promising results .…”

“…Transforming growth factor beta 1 (TGFβ1) is present instead of TGFβ2/3, which in turn can activate IGF-1 secretion and, thus, have an impact on the functional recovery of the tendon (Chang et al, 2000a;Klein et al, 2002). PDGF and bone morphogenetic protein 12 (BMP-12) are moderately expressed overtime in the midsubstance of the tendon (Wuergler-Hauri et al, 2007).…”

Adhesions in a murine flexor tendon graft model: Autograft versus allograft reconstruction

“…3,[15][16][17][18] Other studies have focused on molecular treatment of the flexor tendon injury to provide adhesion-free healing via the delivery of anti-scarring adjuvants that inhibit the effects of TGF-b and bFGF among other factors. [19][20][21][22][23] Despite their promise, these approaches remain experimental and have yet to yield a clinical application, 3 largely because our understanding of the molecular mechanisms involved in the formation of adhesions after flexor tendon injury and grafting remains incomplete. The novel mouse model of FDL tendon grafts offers a quantitative tool to not only examine the biomechanical aspects of flexor tendon grafts, but also to potentially elucidate the molecular events involved in repair and subsequent adhesion formation via the use of transgenic mouse models of gain and loss of function.…”

“…21,24 By contrast, the Gliding Coefficient is based on joint flexion data over a range of applied loads that would cause a maximum 758 flexion in a normal unoperated MTP joint. The test offers information about the joint ROM (the plateau) and the resistance to flexion with increased loading (the gliding coefficient).…”

Modulation of peritendinous adhesion formation by alginate solution in a rabbit flexor tendon model

“…6 It is therefore considered that if an intrinsic response could be stimulated at the early stage of tendon healing, the outcome of tendon repair would be preferable with regard to reducing peritendinous adhesion. Based on this idea, a wide range of substances, including fibrin sealant, 11 5-fluorouracil, 12 sodium hyaluronate, 15 aprotinin, 16 and TGF-␤1 neutralizing antibody, 17 have been experimentally applied to the tendon repair, with the aim of reducing extrinsic healing and stimulating the intrinsic mechanism. However, problems such as high cost of raw materials, potential side effects, and limited bioavailability have prevented widespread clinical use of these agents.…”