Introduction

Anterior cruciate ligament (ACL) reconstruction is a frequent and highly performed orthopedic surgery in sports medicine, with over 60,000 to 150,000 ACL reconstructions performed annually in the United States alone.

This surgery aims to restore knee joint stability and function by replacing the torn ACL with a new tissue graft in patients with ACL injuries (common among active people and athletes). ACL is an important ligament in the knee that stabilizes your knee joint by preventing your shinbone from sliding forward during high-impact athletic activities like jumping, cutting, and pivoting.  

Though ACL reconstruction is a standard treatment for people with ACL injuries, its graft healing process is slow and takes several months to a year for full recovery. Various research studies reported that biologics may help accelerate the graft healing process.

In this blog, we will briefly explore the graft healing process, including its stages and the mechanical properties of the healing graft, and take a closer look at whether biologics can truly speed up the process.

Graft Healing After ACL Reconstruction

As per the research studies, the graft healing process occurs in three stages in two main areas: the graft tunnel interface and the intra-articular graft after ACL reconstruction. Each of these areas undergoes distinct biological processes that ultimately determine the success of the reconstruction. 

First, let’s review the biological processes in the graft tunnel interface after ACL reconstruction surgery. 

• Graft Tunnel Interface

The graft tunnel interface is the point where the new ACL graft (replacement tissue) connects to the bone after reconstruction surgery. Typically, during surgery, the doctor drills holes (called tunnels) into the thigh bone (femur) and shin bone (tibia). Then the tendon graft is fixed to the bone tunnels and secured in place using staples, sutures, cross-pins, or interference screws.

The healing process in the graft-tunnel interface is critical as it provides initial stability to the graft and facilitates its integration into the bone. The graft-tunnel interface undergoes the following healing processes:

• Inflammation Phase

This phase starts shortly after the ACL reconstruction surgery. Your body triggers an inflammatory response, in which certain immune cells like neutrophils and macrophages travel to the injury site (implanted graft). These cells help clear debris (dead cells) and prepare the site for healing and repair by releasing cytokines molecules that signal other cells (or growth factors) for tissue healing. 

• Fibrovascular Integration

Over the next few weeks, fibrous connective tissue and new blood vessels begin to form between the graft and the bone to supply essential nutrients to the cells and create a scaffold for further healing.

• Formation of Bone

Over several months, new bone forms around the graft, and it is secured in place. This process is similar to fracture healing and is essential for long-term stability.

The graft-tunnel interface typically takes 6-12 weeks to achieve initial stability, but complete integration can take up to 6 months or longer. However, if the graft fails to integrate properly, it can lead to graft failure or instability in the knee.

• Intra-articular Graft – Ligamentization

The intra-articular graft, which lies within the knee joint, undergoes a process called ligamentization, where a graft begins to remodel itself, which means changing the way it looks to more closely resemble the original ACL. 

The ligamentization process occurs in three phases, which are as follows: 

1. Early Phase (0-4 Weeks)

During the early healing phase following graft implantation, the tendon graft undergoes necrosis (cell death) due to the lack of blood supply. This also decreases the cell number (hypocellularity).

The graft necrosis leads to a release of growth factors, which, in turn, stimulate cell migration and proliferation as well as extracellular matrix (ECM) synthesis and revascularization in the next stage.

1. Proliferation Phase (4-12 Weeks)

In the proliferation phase, the cellular activity increases, and the graft tissue is repopulated with cells coming from surroundings (i.e., synovial fluid, the native ACL remnant, or bone marrow elements released during bone tunnel drilling). These cells enhance new blood vessel formation to gain nutrient supplies, and new collagen fibers are synthesized. 

Compared to the early phase, the graft gains some strength but is still relatively weak and vulnerable to injury.

1. Maturation Phase (12 Weeks and Beyond)

This phase, the longest and most critical stage of ligamentization, starts 3 months after the ACL reconstruction surgery. The graft undergoes remodeling to achieve the mechanical properties and structure of the native ACL. Moreover, bone maturation occurs simultaneously with remodeling of the intra-articular portion.

In this phase, the graft gradually gains strength and stiffness, but it may take up to 12-24 months to fully mature and become very similar to the native ACL.

Mechanical Properties and Timeframe for Ligamentization

The mechanical properties of the graft vary greatly throughout the process of ligamentization. Initially, the graft is strong due to the properties of the donor tissue (e.g., patellar tendon, hamstring tendon). However, as the graft undergoes necrosis and revascularization, its strength decreases, reaching a low point at around 6-8 weeks post-surgery, followed by a gradual increase in strength and stiffness throughout the maturation phase.  

By 6 months, the graft typically regains about 50-60% of its original strength, and by 12-18 months, it may approach the strength of the native ACL. However, the graft never fully replicates the mechanical properties of the original ACL. 

In fact, various studies have shown that a new ACL never fully gains the same biological or mechanical properties as the original ACL, which means that an ACL reconstruction surgery can get your knee very close to perfectly healthy. However, it will still never be quite as healthy as it was before the actual injury.

Can Biologic Augmentation Speed This Up?

Research studies on the use of biologics (such as mesenchymal stem cells (MSCs), growth factors, and platelet-rich plasma) to accelerate the graft healing process after ACL reconstruction are still ongoing. 

Let’s read what the recent research evidence has reported regarding the use of biologics to improve the healing outcomes in both the graft-tunnel interface and the intra-articular graft. 

• Graft Tunnel Interface

• Platelet-rich plasma (PRP)

PRP contains a high concentration of growth factors and cytokines that stimulate bone formation and enhance graft integration. For instance, a retrospective study (including 85 patients) reported that patients who received PRP injections at both ends of tendon grafts showed increased tendon-bone healing in grafts compared to controls. 

However, some studies have shown mixed results, but some evidence suggests that PRP may accelerate early healing.

• Platelet-Rich Fibrin (PRF)

Similarly, PRF, a bioactive material, can potentially enhance tendon-to-bone healing by promoting the formation of fibrocartilage and new bone formation, as reported by controlled laboratory and research studies. 

• Bone Morphogenetic Proteins (BMPs)

BMPs are potent osteo-inductive agents that promote tendon-to-bone healing to obtain early formation of tendon-bone insertion, similar to that of normal ACL. Studies have demonstrated that BMP-2 and BMP-7 improve bone formation around a tendon graft, but human studies are still limited.

• Stem Cells

Mesenchymal stem cells (MSCs) have the potential to differentiate into bone-forming cells and enhance graft integration. MSCs also stimulate the formation of a native-like fibrocartilage in the graft-bone interface. 

Several studies have shown promising results of using MSCs to enhance the graft healing process, but more studies are needed to determine their efficacy.

• Intra-Articular Graft

Some of the most studied techniques that have shown promising results in accelerating ligamentization and improving the mechanical properties of the graft include:

• PRP and Growth Factors

In addition to the graft-tunnel interface, PRP and growth factors can also speed up the ligamentization process. For example, a recent study involving 80 patients recovering from ACL surgery found that those who received PRP treatment experienced faster healing and better knee function after six months than those who received standard care. This suggests that PRP could be a helpful addition to recovery, offering patients a chance to heal more effectively and get back to their daily lives sooner. 

Similarly, another study reported that PRP may improve intra-articular graft maturation.

• Bone Marrow-derived Stem Cells

MSCs may also play a role in intra-articular graft healing by promoting cell repopulation and collagen remodeling. Moreover, animal studies have shown that stem cell therapy enhanced the biomechanical and histological properties of the tendon graft after ACL reconstruction.

For example, a recent study published a new ACLR technique using both biological (bone marrow aspirate concentrate [BMAC] and demineralized bone matrix [DBM]) and mechanical augmentation (suture tape augmentation [STA]) to potentially accelerate graft healing, expedite recovery, and reduce graft failure rates. 

Following this, another study reported that patients who received ACLR with BMAC, DBM, and STA showed faster functional outcomes including range of motion (ROM) and improved limb symmetry compared to non-augmented ACLR patients. 

Takeaway

Even though biological augmentation has much potential, it is important to remember that some evidence is still developing. Since they are still in the experimental stage, many of these methods are not yet commonly used in clinical settings.