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Knee Surg Sports Traumatol Arthrosc (2008) 16:834–842

DOI 10.1007/s00167-008-0560-8

KNEE

Graft remodeling and ligamentization after cruciate ligament
reconstruction
S. U. Scheffler Æ F. N. Unterhauser Æ A. Weiler

Received: 29 October 2007 / Accepted: 24 April 2008 / Published online: 31 May 2008
Ó Springer-Verlag 2008

Abstract After reconstruction of the cruciate ligaments,
replacement grafts have to undergo several phases of
healing in the intra-articular graft region and at the site of
graft-to-bone incorporation. The changes in the biological
and mechanical properties of the healing graft in its intraarticular region are described as the ligamentization
process. Significant knowledge has been added in the
understanding of the several processes during the course
of graft healing and is summarized in this article. The
understanding of the spatial and time-dependent changes as
well as the differences between the different models of
graft healing are of significant importance to develop
strategies of improved treatment options in cruciate ligament surgery, so that full restoration of function and
mechanical strength of the intact cruciate ligaments will be
achieved.
Keywords Cruciate ligaments  Graft remodeling 
Ligamentization

S. U. Scheffler (&)  F. N. Unterhauser
Center for Musculoskeletal Surgery, Charite´,
University Medicine Berlin, Charite´ Campus Mitte,
Chariteplatz 1, 10117 Berlin, Germany
e-mail: sven.scheffler@gmx.net; sven.scheffler@charite.de
F. N. Unterhauser
e-mail: frank.unterhauser@charite.de
A. Weiler
Zentrum fu¨r Spezielle Gelenkchirurgie, Am Tegeler Hafen 2,
13507 Berlin, Germany
e-mail: weiler@arthroskopie.de

123

Introduction
The successful reconstruction of ligamentous structures in
the knee joint, such as the anterior or posterior cruciate
ligaments, requires understanding of several factors. These
are the mechanical properties of the selected graft tissue as
well as the mechanical behaviour and fixation strength of
its fixation materials. However, it is equally important
to understand the biological processes that occur during
graft remodeling, maturation and incorporation. They are
directly affecting the mechanical properties of the knee
joint after cruciate ligament reconstruction and, therefore,
determine the rehabilitation and time course until normal
function of the knee joint can be expected.
Several studies have analyzed the various changes that
occur during graft healing [1, 6, 8, 10, 14, 19–22, 25, 26,
29–33, 38, 39, 41, 44–46, 53, 56]. Two main sites of
healing exist that should be separately assessed, since their
biological processes vary substantially: the intra-articular
graft remodeling, often referred to as ‘‘ligamentization’’
and the intra-tunnel graft incorporation, which develops
either by bone-to-bone or by tendon-to-bone healing.
In the beginning of the last century Wilhelm Roux has
already described the ‘‘law of functional adaptation’’,
elucidating on the fact that ‘‘an organ will adapt itself
structurally to an alteration, quantitative or qualitative in
function’’ [39], laying groundwork for later research on
ligamentization. He observed that soft-tissue structures,
such as ligaments and tendons, undergo specific changes in
their mechanical and biological properties, when they are
exposed to a different mechanical loading and biological
environment. Amiel et al. were among the first authors [2,
3], who analyzed the specific functional adaptation of an
ACL replacement graft and postulated the term ‘‘ligamentizaton.’’ They found a continuous development of a

since characteristic differences remained between replacement grafts and intact ACL. result in cell migration and proliferation as well as extracellular matrix synthesis and revascularization [21. which. 32. 51]. Proliferation phase of graft healing The proliferation phase is characterized by a maximum of cellular activity and changes of the extra-cellular matrix. 57]. 4. The remodeling process already begins between the 1st and 2nd week when an influx of cells can be seen into the graft’s periphery [7. illustrate these findings [7]. During the early healing phase the mechanical strength of the ligamentous reconstruction is becoming significantly lower than that at the time of implantation and continuous to losing mechanical strength until around the 6th postoperative week. the importance of mechanical loading for the healing tissue has been shown. This study laid the foundation for increased research efforts to improve the understanding of the basic science of intraarticular ACL graft healing or ligamentization. 42] that this time period is marked by increasing necrosis. Even though beginning disintegration of collagen fibrils and their orientation can be observed as early as 3 weeks after reconstruction [7. no graft revascularization can be observed [4. in turn. contrary to only a slight increase in tendon stress. This loss in tensile strength was associated to splitting and defragmentation of collagen bundles as early as 2 weeks. 32. the time of most intensive remodeling and revascularization and finally. While at the early healing phase between 2 and 4 weeks the lack of sufficient graft incorporation is the weak site of the reconstruction with consistent failure by graft pullout [13. interleukin 6 as well as chemokines that trigger a cascade of growth factors expression. Early graft healing phase The biological changes from the time of cruciate ligament reconstruction until around the 4th postoperative week can be outlined as the early graft healing phase. 22. On the other side. overloading of the graft can also lead to impaired graft healing. followed by a phase of proliferation. Graft necrosis leads to a release of several cytokines. 24]. however the most adequate magnitude at the varying phases of healing is still not clearly defined. Kleiner et al. Its intensity increases continuously with maximum remodeling activity during 835 the proliferation phase between 4 and 10 weeks. Therefore. Differences between basic science in vitro and in vivo animal studies and human biopsy studies will be explained and the importance of adequate postoperative care following cruciate ligament reconstruction will be highlighted. especially for the early healing period. [31] found a significant loss of tensile strength at 1 week already with further deterioration until 6 weeks of healing when stress depriving the graft in vivo. 41]. 55]. Arnoczky [4] suggested that preservation of the ACL stump and the Hoffa fat pad might be beneficial. mainly in the centre of the graft and hypocellularity. a shift toward the intraarticular graft region must be noted during the proliferative healing phase when the maximum remodeling activity seems to interfere with the mechanical strength of the healing graft [13. Most authors agreed. Ultrastructural cell changes. Amiel described this process as a transformation. They hypothesized that the source of cells were either the synovial fluid. as well as macroscopic swelling and increased cross-sectional area. Since cellular 123 . 7. Even though there is deterioration in mechanical strength of the healing graft. a ligamentization phase that provided characteristic restructuring of the graft toward the properties of the intact ACL. 22]. which did not significantly impair the mechanical strength [46]. which will be outlined in this manuscript. the graft’s overall collagen structure and its crimp pattern are still maintained [3]. [23] and later Yoshikawa et al. [57] were able to demonstrate that all original graft cells did not maintain viability and were completely replaced by 2–4 weeks. found that a substantial increase of tendon stress resulted in substantially reduced tensile strength as early as 3 weeks. 32. which are paralleled by the lowest mechanical properties of the reconstructed knee joint during healing. not as a restoration of the native ACL. using different in vivo animal models [3. It is agreed that ACL graft healing can only progress if mechanical loading occurs. At the same time. interleukin 1-b. They defined several phases of characteristic changes: an early phase with central graft necrosis and hypocellularity and no detectable revascularization of the graft tissue. 14]. cells from the stump of the native ACL or bone marrow elements originating from drilling maneuvers. Most authors have adapted the different phases of healing and have added significant knowledge to the principle of ligamentization. It was recognized that the combined healing of the intra-articular remodeling and the intra-osseous graft incorporation were dictating the mechanical function of the joint after ACL reconstruction. 41. This explains the only slow decrease in the mechanical properties of the graft at this early healing phase [7. 15. such as mitochondrial swelling. dilatation of the endoplasmic reticulum and intracytoplasmic deposition of lipids.Knee Surg Sports Traumatol Arthrosc (2008) 16:834–842 patellar tendon graft with different biological and mechanical properties than the ACL into a structure that closely resembled these properties of the intact ACL. Ohno et al. 23. such as TNF-a. Tohyama et al.

10. a graft hypercellularity (4009) with b cellular invasion into the periphery and remaining acellular areas of the graft (1009) and c hypervascularity at the areas of increased cellular density (1009. 54] in the healing ACL graft. such as bFGF. this phase is referred to as the proliferation phase of ACL graft healing. 40. a more even distribution of cells throughout the graft develops thereafter. However. 55]. Slowly. These contractile 123 fibroblasts are progressively expressed during the first three postoperative months [40. confirming the descriptive findings of other previously published studies. are also found during this healing phase [50. 18. they did not find a significant increase in vascular outgrowth before the 4th and 8th week. However. [56] showed up-regulated expression of VEGF. 55]. An increased number of specific fibroblasts. with the most characteristic changes occurring between the 4th and 12th postoperative week. It has been a matter of debate. so-called myofibroblasts. 1 ACL graft at 6 weeks of healing (Masson–Goldner trichrome staining). immunohistochemistry. During this phase. [49] independently showed that revascularization progresses from the periphery of the graft toward the entire graft diameter at the end of the proliferation phase around 12 weeks of healing (Fig. 49. In the intact ACL they seem to be responsible for the crimping structure of the collagen fibers [28].g. 3). At the same time of increased cellular proliferation. which is triggered by hypoxia during the avascular necrosis of the early healing phase [19]. already at 2–3 weeks post reconstruction. but this also induced a significant deterioration to the mechanical . 49. [24] found that the release of these growth factors peaks between the 3rd and 6th week and almost completely ceases at 12 weeks of healing. Cell numbers are still increased. e. Kuroda et al. enhanced cellular infiltration and fibroblast expression during the proliferation phase of healing. cellularity constantly increases and substantially surpasses that of the intact ACL as it was observed in various in vivo animal models [5. Recent studies found that up-regulation of revascularization. Vascular density then returns to values of the intact ACL during the phase of ligamentization by 6 months [35.836 Knee Surg Sports Traumatol Arthrosc (2008) 16:834–842 Fig. by exogenous application of VEGF. 51] (Fig. TGF-b-1 and isoforms of PDGF to initiate and maintain graft remodeling. there is a continuous transition between these two phases. These fibroblasts have the ability to exert isometric tension on its surrounding cellular and extra-cellular matrix. F VIII) proliferation has already begun during the early healing period. Cell clusters are found at the perimeter of the graft around 6 weeks with large acellular areas remaining in the graft’s center (Fig.. These hypercellular regions were shown to consists of mesenchymal stem cells [42] and activated fibroblasts [24] that are actively secreting several growth factors. Petersen [35] and Unterhauser et al. 3). Yoshikawa et al. 1). a potent stimulator of angiogenesis. 54]. 42. It is assumed that this intense revascularization triggers and retains the maximal remodeling activity. whether such increased revascularization is beneficial to the healing of the graft. intense revascularization of the graft tissue is found from the 4th postoperative week on [4. which lends further explanation for the maximum remodeling activity during this proliferation phase. when they seem to be responsible for the restoration of the in situ tension that is required for the later ligamentization process. 49]. but recede toward the intact ACL cellularity at the end of the proliferation phase [40.

23. These findings support the reports of numerous other studies that all found the mechanical properties to be at its minimum around the proliferation phase of healing at 6–8 weeks [5. Bosch et al. At the same time a significant decrease in collagen fibril density was shown. [40]) properties of the graft [57].Knee Surg Sports Traumatol Arthrosc (2008) 16:834–842 837 Fig. 47. 15. 2). 55] (Fig. which is followed by increased collagen synthesis [43] and a subsequent return to values of the intact ACL at 12 weeks [55]. 123 . during the restoration of collagen density a shift can be observed from large diameter collagen fibrils (that are dominating in the intact ACL. 18. also found an increased expression of collagen type III in the healing graft [8]. However. 33]. which might add further knowledge why a full restoration of the mechanical strength of the intact cruciate ligaments has not been observed in any in vivo model even after 2 years of healing. 18. Several other authors were able to relate the increased revascularization [51] and extracellular infiltration [45] to the decline in the graft’s mechanical properties. 48. which were shown to provide less mechanical strength than large diameter fibrils [12. which has progressed since the early healing phase has been identified to play a role in the reduction of the mechanical strength of the healing graft and it is not until the ligamentization phase that a slow restoration of the collagen orientation and crimp pattern can be observed [3. 36. 13. Also. 40. sheep model adapted from Ref. patellar or hamstring tendon graft) to small diameter fibrils [17. 32. 53. the loss of regular collagen orientation and crimp pattern. 6. 42. 55]. 55]. 2 Change in collagen crimp during graft healing (polarized light microscopy 2009. 40.

It was shown in animal studies that cellularity slowly returns to values of the intact ACL between 3 and 6 months after reconstruction [10. the remodeling activity of human ACL grafts seems to be reduced. The typical ovoid shape of metabolically active fibroblasts slowly changes into the less metabolically active shape of linear spindle like fusiform cells that are normally seen in the intact ACL. e. While the healing phases of animal models (graft necrosis. dog and sheep models [3. 51]. 55] (Fig. Ligamentization phase of graft healing The ligamentization phase follows directly after the proliferation phase and involves the ongoing process of continuous remodeling of the healing graft toward the morphology and mechanical strength of the intact cruciate 123 Knee Surg Sports Traumatol Arthrosc (2008) 16:834–842 ligaments. However. Ng et al. suggesting survival of portions of the original graft. whether a full restoration of the biological and mechanical properties of the intact ACL is possible or whether it is more a transformation of graft tissue that resembles but not fully replicates the properties of the intact ACL. but even after 2 years its frequency stays increased compared to the intact ACL as shown in sheep [40. but did not seem to be as excessive as in the animal model [20]. 54]. 37]. revascularization) are also found in human ACL graft biopsies [20. 30. and collagen cross-links. The change from a bimodal distribution of small and dominating large collagen fibers of the patellar or hamstring tendon graft to a unimodal pattern of only small collagen fibers of the healing graft does not change during the phase of ligamentization [18. It has also been shown in rabbit. 54]. could not be confirmed in humans. Large areas of the human healing graft seem to stay unchanged displaying tendinous structure with normal collagen alignment and crimp pattern [20]. 49. 34]. which corresponds to the findings in animal models. recellularization. a patellar tendon or free soft-tissue tendon graft. 10. which might result into early stretch-out of the ACL reconstruction. 51. but returned to values of the intact ACL by 3 years. Several human biopsy studies found significant differences between the remodeling activity of human ACL grafts during the first 3 months and the healing graft in animal models. The increased synthesis of collagen type III of the proliferation phase decreases during the ligamentization phase. Rougraff et al. Also.g. The heterogeneous composition of collagen fibers of varying diameter of the intact ACL is never restored [1]. suggesting that the ligamentization process might continue longer than previously expected [30]. revascularization and changes in collagen crimp and composition during the early healing and proliferation phases [58]. 51. 25. 37]. that the healing graft undergoes a transformation from its initial tissue properties. A clear endpoint of this phase cannot be defined since certain changes still occur even years after reconstruction. but without compromising graft integrity. [37] found viable intrinsic graft cells in human biopsy specimens at all time points between 3 and 8 weeks after ACL reconstruction. which microscopically resembles the appearance of the intact ACL around 6–12 months after reconstruction [40. 52] for certain extra-cellular matrix proteins. Type III collagen is normally found in . 40. These areas were histologically identical to the native graft tissue. It will have to be determined what loading of the healing graft is most appropriate at this phase of healing. A regular crimp of the collagen fibers can be seen as early as 6 months. It must be high enough to stimulate graft cells to produce cellular and extra-cellular components for preservation of graft stability. 30] as early as 6 months. Collagen fibers regain their organization into fascicles after complete loss of alignment and initial dense packaging during the ligamentization phase. especially regarding the extra-cellular matrix. It is still a matter of debate. While certain biological features of the healing graft have been reported to return to the morphology of the intact ACL.. 40. 3). where necrosis or degeneration never involved more than 30% of the graft’s biopsies. 4). recellularization. to properties of the intact ACL during this ligamentization phase [3. but continues to sustain in significantly higher concentrations than in the intact ACL even at 2 years [7. 56] (Fig. the excessive graft necrosis observed in animal studies. The complete loss and replacement of all intrinsic graft cells by extrinsic cells has not been observed shown in the human healing ACL graft [20. such as glycosaminoglycans. human biopsy studies confirm the remodeling cascade of (very limited) graft necrosis. Neovascularization was also found. suggesting that also the human ACL graft might have its lowest mechanical strength around 6–8 weeks postoperatively. Vascularity throughout the graft decreases and returns to values of the intact ACL and vessels become evenly distributed throughout the entire graft between 6 and 12 months [4. several differences remain. These findings might explain why early loading and aggressive rehabilitation during the first three postoperative months after human ACL reconstruction did not result in a significant increase in failure rates. 49. Loss of collagen organization was only detected in areas of neovascularization in human biopsies. But their initial loss in collagen crimp and strict parallel alignment of the proliferation phase is only partially restored.838 The substantially reduced mechanical properties of healing grafts in animal models seem to contradict the successful clinical outcomes after ACL reconstruction with immediate aggressive rehabilitation in humans. found in a dog model of ACL reconstruction that type III collagen also remained increased in the remodeling graft at 1 year.

3 Revascularization during graft healing Fig. especially important to understand why all animal models demonstrated significantly lower mechanical properties of the healing 123 . The findings of persistency of small diameter collagen fibrils and increased type III collagen content are. 4 Collagen remodeling of a sheep ACL graft (continuous shift from the bimodal collagen diameter distribution of the initial soft-tissue graft (sheep long flexor tendon) to a unimodal small diameter collagen fibril distribution at 52 weeks and comparison to the heterogenous collagen fibril diameter of the intact ACL) scar or early ligamentous repair tissue and has a lower mechanical strength than type I collagen.Knee Surg Sports Traumatol Arthrosc (2008) 16:834–842 839 Fig. therefore.

they found that overall degeneration. Other studies [1. in the animal model that ACL grafts undergo a process of adaptation rather than full restoration of the intact ACL’s biological properties. biopsy specimens taken at 6 months still showed significantly different cross-link ratios of the healing grafts compared to the intact ACL. Neovascularity and hypercellularity only slowly appeared and carried on until 10 months. the timeline of these biological changes appears to be different between human and animal models. 51. This underlines the differences in remodeling activity between humans and animal models. 18. 53]. 10. Some non-biopsy studies that evaluated graft revascularization. which is different from the earlier crosslink restoration found in animal models. 13. Interestingly. Regardless of any model. Zaffagnini et al. but that the extent of vascularity might be below the threshold 123 Knee Surg Sports Traumatol Arthrosc (2008) 16:834–842 detectable with gandolinium enhanced MRI. 38] even found increased cell counts and differing fiber alignment beyond 3 years with graft being indistinguishable from the intact ACL as late as in 3 year biopsies. 51. Overall. 30.g. 13. Regarding collagen remodeling. 6. characteristic differences. whether human or animal. But until now there has not been a single animal study that demonstrated that the structural properties (e. which might allow for the assumption that the mechanical properties are also substantially higher than in animal models during the first three postoperative months. [27] found that the collagen cross-links (dihydroxylysinonorleucine/hydroxylysinonorleucine ratios) of patellar tendon and hamstring tendon autografts had changed from time 0. in animal models overall restoration of graft integrity and histological appearance is completed between 6 and 12 months of healing. [1] independently confirmed the findings of Weiler et al. However. when they were significantly different from the intact ACL. 32. 30.. They concluded similar to the findings by Bosch et al. which differs from observations in animal models. could not detect any revascularization except from the periligamentous ACL graft tissue. [38] analyzed 23 biopsies of human patellar tendon ACL reconstruction between 3 weeks and 6. acquiring similar morphology of the intact ACL. [51]. [55] and others [18. Graft integrity is much less compromised during the early healing and proliferation phase in human ACL grafts. who analyzed his sheep ACL reconstruction also with gandolinium enhanced MRI and could detect significantly upregulated neovascularization during the first three postoperative months. using gandolinium enhanced MRI during the course of healing for 2 years [16]. 53]. They found that hypercellularity and hypervascularity had not returned to control intact ACL values before 6–12 months with fiber alignment being restored around 6 months. 25] that patellar tendon [1. 40. Cho et al. No details are given on ultrastructural differences between the healing graft and the intact ACL in this study. Human biopsy studies that analyzed changes of the extracellular matrix observed changes that are in line with the findings of animal models. to 1 year postoperatively. especially in extra-cellular matrix composition. Rougraff et al. In summary. They found that necrosis took place in much smaller areas of the graft at 3 and 6 week biopsies than it was shown in animal models. but others observed significant lower ap-laxity even 3 years after reconstruction [29]. However. failure load. when both grafts had acquired cross-link ratios that were identical to the intact ACL. confirming the ligamentization process found in animal models. Some studies were able to show that these compromised mechanical properties would still allow for restoration of anterior–posterior (ap)laxity to the laxity of the contra-lateral intact ACL [53].5 years postoperatively. Identical findings were made by Falconiero et al. [9] and Abe et al. However. even though all human biopsy studies have shown that neovascularisation does occur. 40. 58] and hamstring tendon [9] ACL grafts showed a replacement of large by small diameter fibrils. It has been shown that the mechanical properties of the ACL reconstructed knee joints improve substantially during the phase of ligamentization and reach their final maximum properties at around 1 year. but the intensity of graft remodeling in humans is significantly lower than in animal models. the ligamentization phase seems to be rather similar in both models in terms of biological progression. which did not change even after more than 2 years after reconstruction. Rougraff et al.840 graft than that of the intact ACL even after long-term healing of up to 2 years [7. [38] concluded that the proliferation phase seemed to be delayed compared to animal models with the highest remodeling activity between 3 and 10 months. remain and do not reach the initial mechanical strength of the intact ACL. increased until 6–10 months and only slowly disappeared between 1 and 3 years postoperatively. While human biopsy studies showed substantial differences from animal models for the proliferation phase. an adaptation of the healing . stiffness) of the healing graft could surpass 50–60% of the intact ACL [5. [11] using patellar tendon and hamstring tendon ACL reconstruction. This also confirms the differing timeline of the remodeling of human ACL grafts. Full histological maturity was not found before 12 months of healing. even though limited compared to animal models. confirming the observations made in animal models. This is also substantiated by the mechanical properties that reach their maximum strength around 12 months without any further significant changes thereafter. 29. It is important to understand that the results of graft healing studies in animal models cannot be directly applied to the human ACL patient. The biological processes are similar. which is in contrast to the findings of Weiler et al. [58]. Marumo et al. 18.

knee joint motion will provide the same mechanical stimulus to the healing ACL graft as to the intact ACL. J Bone Joint Surg Am 73(2):201–213 18. Goradia VK et al (2000) Tendon-to-bone healing of a semitendinosus tendon autograft used for ACL reconstruction in a sheep model. J Orthop Res 23(6):1425–1432 22. J Bone Joint Surg Am 64(2):217–224 841 5. it seems to be most important that knee joint mechanics are restored by cruciate ligament reconstruction. Grana WA et al (1994) An analysis of autograft fixation after anterior cruciate ligament reconstruction in a rabbit model. (b) developing biological treatment options that impact on graft healing especially during the early and proliferation phase to optimize extra-cellular matrix remodeling and avoid excessive remodeling activity that might impair mechanical integrity of the healing graft and (c) to better differentiate the ‘‘good’’ from the ‘‘bad’’ remodeling changes. This is confirmed by human biopsy studies that revealed an intact. 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