Biologics in Foot and Ankle Surgery

Role of Biologics in Achilles Tendinopathy

Despite the Achilles tendon being one of the strongest tendons in the human body, it is one of the most frequently ruptured lower limb tendons and comprises roughly 20% of all large tendon injuries. Unfortunately, healing of Achilles tendon has had unpredictable outcomes due to its limited bloody supply that diminishes usually after the third decade. Tendon healing often results in a fibrovascular scar and tendon that is weaker than the previously uninjured healthy tendon. This obviously leaves the tendon at increased risk of rerupture and stiffness. This has led to the investigation of biologics for Achilles tendinopathy. Although the role of biologics in Achilles tendinopathy is still under study, we will explore current findings of tendon healing with platelet-rich plasma (PRP) and bone marrow aspirate concentrate (BMAC). We will also discuss the use of acellular dermal matrices and their use in strengthening Achilles tendon rupture.

PRP and BMAC: Is There a Role?

PRP has received much more attention recently in its role to stimulate healing and even revascularization with in vitro studies with growing evidence in its use in the setting of foot and ankle pathology. PRP is defined as plasma with a twofold or more platelet concentration above baseline level. In vitro studies have shown PRP to release platelet-derived growth factors (PDGFs), multiple transforming growth factors including TGF-B1/B2, and growth factors used in healing and stimulating the inflammatory response. The platelets also contain cytokines and chemical mediators such as histamine, fibrinogen, fibronectin, and serotonin to help induce the inflammatory response. Biologic studies have also shown that PRP can enhance type I and type III collagen synthesis by tendons. The use of PRP has been investigated in mice with positive results. Kaux et al. examined the use of PRP injection in mice after Achilles tendon rupture and found that those with PRP injections had earlier tendon healing and stronger mechanical resistance at 30 days.

PRP has been used in humans as well for chronic Achilles tendinopathy with mixed results. de Jong et al. found that patients with chronic Achilles tendinopathy had no significant clinical or ultrasonographic tendon differences with PRP versus placebo at 1 year. PRP may have more of a role in assisting in the healing of partial or full-thickness tendon tears. Several mice studies have demonstrated increased neovascularization and accelerated healing with Achilles tendon tears. Filardo et al. presented a case report of a competitive athlete with partial Achilles tendon rupture who was treated nonoperatively with PRP injections. Their study found that with three injections within 3 weeks, the patient was able to go back to baseline sports performance within 75 days of the initial injury. Plasma rich in growth factors has also been examined and has demonstrated superior tendon healing compared to control. Despite the more promising results of PRP in animal studies, its effect on human studies have been mixed. The literature has shown that PRP may be more useful with healing of the acute tendon rupture rather than chronic tendinopathies.

Along with PRP, bone marrow aspirate has also been used for possible treatment of Achilles tendinopathy. Bone marrow aspirate differs from PRP in that it contains mesenchymal and hematopoietic stems cells along with PDGFs. The bone marrow concentrate is done via aspiration usually from the iliac crest and produced by centrifugation, isolating stem cells to be reinjected into the Achilles tendon. Stein et al. examined the use of bone marrow aspirate in a small cohort of patients who underwent open Achilles tendon repair with BMAC injections and found no rerupture, with 92% of patients returning to their sport at a mean of 5.9 months. The use of bone marrow cell injection has also been supported in animal studies. Okamoto et al. compared the use of bone marrow cell transplantation versus mesenchymal stem cells in mice after Achilles tendon rupture. They found significantly increased type III collage at 1 week and type I collagen at 1 month with bone marrow cell transplantation. Despite the early benefits seen in both the clinical and animal studies, long-term data in its use in Achilles tendon are not yet available. This will help assess the risk of these stems developing into tumor lineages which is a potential concern of BMAC.

Acellular Dermal Matrices for Strengthening Repairs

More recently, acellular dermal matrices (ADMs) have been examined for their use in Achilles tendon repair. ADM is derived from cadaveric skin with techniques that allow preservation of the extracellular matrix. The matrix is used to act as scaffold for reepithialization, neovascularization, and fibroblast proliferation without theoretically inducing an inflammatory response. The acellular matrix contains collagen, elastin, and proteoglycans along basement membrane connective tissues which allow for integration and support into the host tissue. ADMs allow for mechanical support while enhancing healing through host cell infiltration. Lee et al. examined the effectiveness of acellular dermal tissue matrix as an augment to Achilles tendon repair which was sutured circumferentially around the tendon. They saw no cases of rerupture or recurrent pain at 20 months, with an average time to baseline activity by 11 weeks.

Rerupture of an Achilles tendon repair after use of ADM augment has been reported. Bertasi removed part of the ADM after rerupture for histological examination, which showed excellent attachment of the ADM to the paratenon at 8 weeks postoperatively. They also identified vast vascularization in the graft paratenon interface. Their study showed excellent integration of the matrix with remodeling of the ADM into the tendon. The use of ADM augments in Achilles tendon ruptures is still in its infancy with limited available long-term data; however, the available studies have demonstrated good results with little complications with in vitro use.

Role of Orthobiologics in Plantar Fasciitis

Plantar fasciitis is among the most common causes of plantar hindfoot pain among sedentary and active individuals in the United States and accounts for nearly 600,000 to 1 million physician visits annually, although this number may be greater. The plantar “fascia” is a thick connective aponeurosis that originates proximally on the medial tubercle of the calcaneus and inserts distally in the form of five distinct bands onto the metatarsal heads and bases of the proximal phalanges. The mechanical function of the plantar fascia is to maintain the integrity of the longitudinal arch of the foot and promote efficient gait via the windlass mechanism. The pathophysiology of plantar fasciitis is likely multifactorial and not currently well understood, although repetitive microtrauma yielding an inflammatory cascade with failed healing likely plays a significant role. The diagnosis is primarily made through a thorough history and physical examination, with advanced imaging used primarily to exclude other likely manifestations from the differential. The symptomatology of plantar fasciitis can be variable but typically involves throbbing heel pain with weight-bearing activities. Therapies such as rest, activity modification, heel-stretching exercises, corticosteroid injections, and nonsteroidal antiinflammatory medications are the mainstay of conservative treatment and function beneficially in the majority patients. Extracorporeal shock wave therapy also may provide benefits in certain patients, but recent randomized control trials (RCTs) showed no significant differences in pain alleviation between treatment and placebo groups. Newer therapeutic strategies have focused on PRP injections with hopes of directly treating the aberrant manifestation of collagen matrix degradation and disordered vascularity in plantar fasciitis by restarting the inflammatory cascade and augmenting the healing response. PRP is the superficial portion of centrifuged blood and is relatively easy to obtain in a clinic setting. A recent systematic review of 12 studies in which PRP was compared to controls of both placebo and corticosteroid preparations showed uniform improvement in symptoms without any complications other than temporary localized pain. Sample sizes within these studies were small and had variable treatment protocols; however, although the data had limitations, the trend toward a beneficial response is promising, especially in the setting of trivial complications. Additional randomized trials also share similar findings. PRP injections may also show measurable symptomatic benefit in patients with recalcitrant plantar fasciitis that is unresponsive to aggressive conservative measures.

Options for Treating the Articular Surfaces

Articular cartilage is a complex tissue isolated from synovial joints and is coated by hyaline cartilage. It is a highly organized substance divided into four unique zones, each with its own unique extracellular matrix (ECM), chondrocyte subtypes, cellular architecture, and varying proportions of proteoglycan and cartilage. The complexity of the cellular subtypes and their unique arrangement coupled with its relatively avascular structure makes articular cartilage defects notoriously difficult to heal. Primary reasons include poor ability of progenitor cells to migrate to the source of injury because of minimal clot formation as well as limited ability for sufficient ECM production by mature chondrocytes. Furthermore, articular cartilage properties vary greatly among the load-bearing synovial joints in the body. Within the ankle, the articular cartilage appears to be thinner than its knee counterpart, and the chondrocytes themselves appear more spaced apart. The ankle joint cartilage also appears more resistant to compressive loads due to a relatively greater proteoglycan concentration within its ECM. Treatment strategies must consider the variability in articular cartilage structure, etiology, time course of presentation, and dimensions of the chondral lesion in question. Options include but are not limited to marrow stimulation via microfracture or direct drilling, auto/allograft osteochondral transplantation, chondrocyte implantation, concentrated bone marrow aspirate, and PRP injection.

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