Introduction

The bone–patellar tendon–bone ligament or “bone-tendon-bone (BTB)” (patellar graft) is a widely used autograft for anterior cruciate ligament (ACL) reconstruction surgery. BTB-ACL reconstruction is associated with anterior knee pain in 4%–60% of patients; this could be improved by adhering to contemporary recovery precepts, thereby reducing postoperative anterior knee pain at the harvest site. There is an existent relationship between donor site defect healing time and anterior knee pain, leading to a rise in the use of alternatives during the past years due to donor site pain after patellar tendon graft harvest. The empty space or gap that is left after graft harvest has been defined as the cause of persistent discomfort and pain at the donor site for several months. Shelbourne et al. discussed the donor site defect, reporting discomfort and pain at the anterior knee. On the other hand, the usefulness of a BTB graft for ACL injuries has previously been proven.

In order to accelerate the healing process, autologous plasma rich in growth factors (PRGF) arises as a new possibility in the preventive treatment of these complications. PRGF are biologically enhanced peptides, which have been shown to accelerate tissue repair.

Studies such as those carried out by Orrego et al., Radice et al., or a previous work by our research group have observed accelerated ligamentous tissue maturation when compared with a control group.

Surgeries that have included the application of PRGF have shown accelerated tissue maturation processes, Orrego et al., Radice et al., and Seijas et al. showed these accelerated processes in ACL reconstruction, whereas Sánchez et al. did the same with the Achilles tendon in athletes. Anoka et al. reviewed the use of growth factors and observed an augmented healing process in medial collateral ligament of the knee. However, although the studies described show improvements in tissue regeneration, caution is advised in their use, and most recommend conducting studies with the highest level of evidence and reproducibility.

The persistent donor site gap after harvesting a central third patellar tendon autograft appears to be correlated with anterior knee pain, suggesting that if PRGF can in fact accelerate the maturation process, one could achieve tissue less susceptible to morbidity, and by doing so, patients could appreciate improved outcomes for the BTB ACL reconstruction technique.

In the present chapter we will assess different studies that have shown how anterior knee pain related to BTB surgery can be improved with biological therapies.

Procedure

Anterior knee pain related to BTB graft harvest has been discussed in numerous studies.

Donor site healing is of special interest, given its direct relation with postoperative anterior knee pain. Lidén studied a group of 14 patients after 10 years’ follow-up, where he observed the persistence of the gap in the donor site, not recommending this technique upon associating poor data in the Lysholm, International Knee Documentation Committee, and KT-1000 tests.

Proctor et al. published a study in 1997 using goats, where they showed that the tissue created after obtaining a patellar graft had some histological, structural, and ultrastructural characteristics that were different from the normal tissue, and that this could have negative repercussions in clinical practice. LaPrade et al. reached the same conclusions in their study with dogs, published in 1997. Linder et al. published a study with dogs in 1994 where they demonstrated the weakness of the remnant patellar tendon once the donor graft had been extracted. The studies that evaluated the patellar tendon donor site of with magnetic resonance showed tissue regeneration in 18 months, but the Rosenberg et al. study showed an absence of said regeneration within 2 years.

On the other hand, other studies concluded that after 2 years of monitoring, the closing of the donor site is complete, by means of control by magnetic resonance imaging (MRI) and ultrasound with anatomical restoration, including the patellar tendon when the paratendon was closed.

Colosimo et al. published in 2001 a series on 15 patients, where they used a graft already used previously, with satisfactory results, concluding that the election of a graft of these characteristics in selected cases could yield good results.

O’Shea and Shelbourne applied the reuse of the patellar tendon in a series of patients, with a minimum of 6 years from the previous surgery. The monitoring process of eight patients over 2 years showed some satisfactory parameters of stability and morbidity, concluding that harvesting a patellar graft a second time could be done with adequate preoperative planning.

Anterior knee pain is probably the most frequent and persistent complication after the reconstruction of the ACL by means of the BTB technique. Although the exact cause has not been determined, various studies indicate a connection between patellofemoral pain and persistent flexion contracture or weakness of the quadriceps.

Sachs et al., found a frequency of patellofemoral pain of 19% in their 126 patients, which relates to flexion contracture. In a study of 226 patients with reconstruction of the ACL, Aglietti et al. also found a positive correlation between the patellofemoral symptoms and the flexion and extension defects of the 5% who had patellofemoral pain.

The reconstruction of the ACL with BTB has created problems in the form of anterior knee pain, hypersensitivity, and inability to kneel in up to 40%–60% of patients.

Shelbourne and Trumper indicated in their study that an adequate rehabilitation achieving early hyperextension could minimize these data, allowing for some rates of anterior knee pain in patients operated by means of the patellar technique, similar to other techniques that did not use the patellar tendon.

Authors like Chang et al. found some very high percentages of satisfaction in the patients with the use of BTB (97%) and even upon comparing the results with other grafts like the allograft, they found the rates of patellar pain to be even greater than with BTB—16% in allografts versus 9% in patellar grafts. However, the same authors acknowledge that in most of the studies reviewed, the percentage of anterior knee pain is associated with the BTB graft.

Various authors have concluded in their studies that it seems obvious that the restoration of articular function and muscular strength may contribute to decreased discomfort and pain in the anterior knee wall.

In the meta-analysis of more than 400 patients performed by Biau et al., a conclusion was reached that the patellar graft offered a lower risk of instability than the hamstrings. Other studies like that by Prodromos et al. reached conclusions that although they were contrary to those presented previously, obtaining greater stability in hamstrings, they attributed this to the femoral anchoring.

It is considered a given that for the correct process of regeneration of a tissue, a multitude of elements must interact, from diverse cell components to diverse proteins, metabolites, and electrolytes, within an adequate environment. During this process, both in the acute inflammatory phase as well as in cell proliferation and remodeling, the platelets play an important role that is not only based on hemostatic capacity but also on chemotactic activity and on growth, morphogenesis, and cell differentiation.

For all these reasons, in the 1990s various studies started to emerge, with their aim being the exploitation of the beneficial effects offered by this cellular type in tissue repair. This stimulated investigation and development in matters of regenerative medicine. There are various stages involved in the tissue repair process, including angiogenesis, tissue proliferation, and the extracellular matrix deposit. The remodeling and maturation processes are combined with the mechanical loads to which the tissue in question is subject.

Growth factors are substances of polypeptide nature, soluble and diffusible, that regulate growth, differentiation, and the phenotype of numerous cell types. These provide the initial signals for the activation of the integral cells of the tissues that surround them. In response to the signs provided by these molecules, the local and infiltrated cells suffer changes in the proliferation, differentiation, and synthesis of proteins with different biological functions. All these phenomena together define the process of cell activation.

These proteins act in an autocrine and/or paracrine manner. They affect cell behavior, joining with specific receptors situated in the cell membranes. Not all the cell phenotypes have the same receptors. Therefore the effect of the growth factors will not be the same in all tissues or in all situations.

The system of obtaining PRGF is not always the same, following different techniques in published studies, yielding therefore noticeably different products without reaching any conclusion with respect to a major or minor efficacy of some versus the others.

The harvesting, preparation, and administration methods also vary. This is why it is very difficult to reach conclusions in the different studies that try to compare the different methods, agreeing that, indeed, being different products, they can give different results.

Autologous platelet preparations have shown the potential of modification to the natural history of tendon and ligament healing in different publications. From a biological standpoint they appear to help the regeneration of tissues that would otherwise have a low healing potential, including their potential for the restoration of biomechanical properties in a similar way to normal tendons and ligaments.

Studies with animals show that the use of PRGF increased cell density and neovascularization without showing side effects or fibrosis. The study on Achilles tendon ruptures in athletes showed that the use of PRGF favored early mobility and earlier return to sport. Studies such as that of De Vos et al. indicate that PRGF has no influence in tendinopathies. Studies like those of Nin et al. or Silva and Sampaio state that the use of PRGF does not alter the results in ACL reconstructive surgeries.

The Taylor et al. review states that the results of these studies can differ from previously mentioned studies, as the techniques employed for obtaining the growth factors differed. The review also states that the De Vos et al. study assesses the results of the application of PRGF in chronic tendinopathies, with just one injection. The works of Nin et al. and Silva and Sampaio assess the development of the ACL graft clinically and by means of images, after 3 months and after 1 year, respectively.

In regard to the donor site, different studies which used magnetic resonance have been conducted, and they indicated that the use of PRGF allows faster tendinous tissue regeneration in the patellar tendon defects in animals as well as in humans.

In 2012 Cervellin et al. published a randomized study monitoring the process for 1 year, where they indicated that the use of PRGF improved knee function when applied in ACL autograft donor site defects. In this same study, there were no observable significant differences in pain at 1-year follow-up.

The study by our group showed that the application of PRGF in the BTB donor site produced faster maturation than the controls that did not receive PRGF in the donor site. And within the same group of patients, the rates of pain were significantly less in the first postoperative months. The evaluation by means of ultrasound and the development of a qualitative classification adapted to this evaluation (Rius classification) allowed researchers to objectify the evolution of the donor site.

Regarding the donor site, Lyras et al. carried out different studies with rabbits showing that the use of PRGF allows for faster regeneration of the tendinous tissue in patellar tendon defects.

The use of platelet rich plasma (PRP) in gel form was studied and reported by De Almeida et al. in evaluations with MRI, obtaining early closing in the group treated with PRP versus the control group, very much in correlation with our study.

Our study which used ultrasound showed how the group that received growth factors evolved toward repair or mature stages at a greater speed than the control group. This acceleration can be observed at the fourth-month ultrasound control, in which we observed complete maturity with statistically significant rates (52% vs. 10%, P = .0037). This difference was diluted in the following months, and significant differences were not found ( Fig. 31.1 ). It is therefore evident that the use of PRGF speeds up maturation, being able to objectify it by means of ultrasound studies.

The plasma rich in growth factors (PRGF) group completes the grade D quicker than the control group. At 4 months we could find significant difference ( P = .0037).

Cervellin et al. in 2012 published a randomized study with a monitoring process of 1 year, where they indicated that the use of PRGF improved the function of the knee, when being applied in donor site defects, in the use of the ACL autograft, but without significant differences in terms of pain. Our results contradicted the results of Cervellin’s study, as in our PRGF group we observed clearly and with statistical significance better pain management from the beginning of the monitoring process.

The control group of this study showed improvement in the management of pain during the first few months, and progressively the numbers plateaued. Toward the ninth month they were very similar, although from the sixth month there were no significant differences. The study of De Almeida et al. evaluated pain very prematurely, and we cannot compare the control figures along the monitoring process because they did not collect. However, in the premature period of the first 24 hours, they showed significant differences in favor of the group treated with PRP. The use of PRGF improves pain early on but not in the long term, a period in which we have results in accordance with the studies of Cervellin.