James M. Cottom, DPM, FACFAS
Florida Orthopedic Foot & Ankle Center
Director, Florida Orthopedic Foot & Ankle Center Fellowship
2030 Bee Ridge Rd Suite B
Sarasota, FL 34239
Britton S. Plemmons, DPM, AACFAS
Fellow, Florida Orthopedic Foot & Ankle Center Fellowship, Sarasota, FL
2030 Bee Ridge Rd Suite B
Sarasota, FL 34239
Submitted for Publication in Clinics of Podiatric Medicine and Surgery 3-2017. This is a peer-reviewed journal.
Foot and ankle surgeons diagnose and treat a plethora of ailments that can address both conservatively and surgically. Many times, patients wish to avoid the operating room at all costs, while others must undergo a surgical procedure to ensure the best prognosis. As the healthcare system in the United States continues to evolve and quality measures are driving reimbursement, improving patient outcomes are what every foot & ankle surgeon strives to accomplish. Numerous orthobiologics have been advocated in the orthopedic literature as an adjunct to routine healing in order to increase the success of a particular treatment regimen. Bone marrow aspirate concentration (BMAC) has gained popularity, particularly in the foot and ankle subspecialty arena as an augmentation to healing in and out of the operating room. Unfortunately, patients are often compromised with multiple co-morbidities including diabetes, smoking, immune-compromised, avascular necrosis that may make healing difficult. BMAC use has been widespread and particularly positive results seen in bone and soft-tissue healing. (1-5).
Bone marrow aspirate has been utilized for the adjunctive treatment of numerous pathologic conditions in the orthopedic community (18). Viable cells are found in aspiration from many different anatomic regions of the body (45). The concentration of these cells has been shown to improve healing due to the increased number of certain important cells (16). There is known benefit of autologous bone marrow concentrate as it has been shown that there is a wide variety of live cells including endothelial progenitor cells, mesenchymal stem cells, hematopoietic stem cells, and other progenitor cells. There are many growth factors as well. These include a platelet-derived growth factor, bone morphogenic protein, transforming growth factor-B, vascular endothelial growth factor, interleukin -8, interleukin-1 receptor antagonist (6-9). Bone marrow is the primary site of mesenchymal stem cells (MSCs) that are multipotent and able aid in soft tissue and bone healing (24-27). MSCs have the innate ability to differentiate into cells types based on the environment they are in. These cellular transitions include fibroblasts, chondrocytes, osteoblasts and myogenic cells.
The safety of harvesting BMAC has been reported (22,23). A complication rate of 0-12% has been documented in the harvesting of BMA in the lower extremity. Bone marrow aspiration from the calcaneus can be performed with ease (Figure 1-). Roukis et al performed a multi-center retrospective observational cohort study looking at 530 patients. All patients underwent harvest of bone marrow aspiration from various sites in the lower extremity. All procedures were determined to be successful with no infection, nerve injury, wound healing or iatrogenic fractures (21).
Theoretical evidence of the utility of BMAC to aid in healing has been reported. We reviewed the orthopedic, sports and foot and ankle literature to review the uses of BMAC in healing common lower extremity conditions.
Recently, there has been a peak interest in the use of BMAC in the foot and ankle literature. This is due to the fact that it is a cost-effective way to deliver a conglomerate of stem cells and growth factors to a particular area. Much of the focus on the benefit of BMAC in foot and ankle surgery is the potential for MSC to differentiate into different tissue derived from mesenchymal cells. Numerous tissues have been found to contain MSCs including bone, adipose tissue, synovium, and blood. (14,15). A multitude of methods has been attempted to harvest, cultivate and deliver MSCs to an area with many of them accruing a large financial burden. Due to the feasibility of bone marrow aspiration, this method has been researched extensively. BMA has been proven to yield only 0.001 – 0.01% of the nucleated cells being MSCs. This surprisingly low number has caused researchers to try and enhance the volume of MSCs, most commonly by the method of the centrifuge in order to reach a concentrate that will yield a higher number of cells. Hedge et al evaluated the efficacy of 3 different BMAC harvesting systems that are available to the market (20). Patients underwent aspiration from bilateral iliac crests using different systems. The aspirate was prepared with the companies proprietary centrifugation system. The Harvest system (Harvest SmartPreP 2, Harvest Terumo BCT, Lakewood, CO) was found to have a significantly greater concentration of progenitor cells compared to the other systems in the study. The method used to harvest the aspiration is important as well. The location of the aspiration has been studied and Hernigou et al compared the use of 10 mL syringe with 50 mL syringe for aspiration of bone marrow. They found a 300% increase in yield of cells in the 10 mL syringe. There was also a higher cell concentration in the in the first mL of the 10 mL syringe compared to the first 5 ml of the 50 mL syringe. This report concludes that a higher cell yield can be gathered with the smaller volume in the smaller syringe (46). A report by Hyer et al analyzed the concentration of osteogenic progenitor cells from several different anatomical sites. Their report found that the anterior iliac crest had a higher concentration of progenitor cells compared to the distal tibia and calcaneus. They also found that the calcaneus and distal tibia yielded no statistical difference in cells. Interestingly, there was no difference in yield with increased age, smoking, sex and diabetes (45). Li et al in a recent report on 10 patients who underwent BMA from the calcaneus and found that there were viable MSCs that were able to differentiate into many different cell lineages when the aspirate was analyzed (28).
Certain cells within BMAC (i.e. MSCs) have been shown to differentiate into osteoprogenitor cells through induction of local proteins and growth factors wherever they are transplanted. A similar response is created when HSCs are placed in the same environment. Through cell-mediated signaling, other host cells are recruited to the area through cell-to-cell communication. These effects have a positive effect on bone healing. Several animal studies have shown positive results with the use of BMAC in osseous healing. Ganikois et al reviewed the literature regarding long bone healing in animal models and found strong evidence to support the use of BMAC for healing augmentation. The thirty-five articles reviewed showed a 100% increase in bone formation in BMAC group compared with the control group (19). In tibia non-unions, Hengiou et al showed that 53 of 60 atrophic non-unions healed with the use of percutaneous transplant of BMAC. Of note, the patients with the 7 non-unions reported a lower concentration of BMAC than the others, further confirming the theory of better results with higher cell concentration (17). Several studies utilizing BMAC to aid in healing in the foot and ankle literature have been reported. Adams et al presented a case report of a medial cuneiform stress fracture, refractory to conservative treatment that was healed with BMAC placed through the canal of a cannulated screw. With standard postoperative protocol, the fracture healed and was confirmed with postoperative CT scan (29).
It has been speculated that high-risk patients with multiple comorbidities have a negative effect on healing rates may benefit from autograft augmentation. Henigou et al in another report compared 86 patients who received iliac crest autograft and 86 patients that received BMAC augmentation at the site of tibia or fibula non-union in the diabetic ankle fracture. Thirty-eight percent of diabetics receiving autograft from the iliac crest failed to demonstrate healing, however, 82% of the patients who received BMAC demonstrated healing at final follow up. Also noted was the increase in complication as the harvest site in the autograft patient cohort. There was a significant difference in the healing of diabetic ankle fracture non-unions in the BMAC group compared to the iliac crest bone graft group (30). Two different studies looked at the time of healing in proximal fifth metatarsal fractures fixed with internal fixation and BMAC. On study found healing to be complete at 5 weeks and the other at 7.5 weeks after the procedure. There were a total of 4 re-fractures in 36 patients between the two reports.
The mechanisms of tendon injury include mechanical stress, inflammatory process, degenerative changes and disorganized healing. One theory is to increase the rate of tenocyte proliferation to strength the recovery and healing of an injured tendon. One method of doing so is to augment tendon healing with BMAC biologic solution. Many mechanisms have been proposed as to the actual cellular healing that is provided by BMAC. Cells contained in BMAC can modulate the healing response of pathologic tendon by controlling inflammation, reducing fibrosis and recruiting other cells, including tenocytes and mesenchymal stem cells. Courneya et al demonstrated that interleukins 4 and 13 were able to stimulate the proliferation of the human tenoctye (36). The contents of BMAC have been shown to include vascular endothelial growth factor and other cells to aid in healing. It should be considered in augmenting tendon repair as most non-traumatic tendon injuries usually begin as asymptomatic injury with a dysvascular component. There is a paucity of information supporting the use of BMAC augmentation in the use of tendon or soft tissue healing in the foot and ankle. Numerous articles looking at animal models support the fact that adding MSCs and other growth factors to a zone of soft tissue injury will aid in the healing and provide superior biomechanical properties of healed tendon (33-35).
Uridizkova et al evaluated rat models who under when non-operative treatment of Achilles tendon rupture. Forty subjects underwent non-operative care without MSC injection and 41 subjects received MSC injection during the postoperative recovery period. An increase in collagen organization, as well as improved vascularization, was found in the group receiving MSC augmentation (35). Yao et al evaluated the impact of MSC-coated suture to augment Achilles repair in 105 rats. Increased strength was noted compared with standard suture repair at different postoperative follow up points. Their conclusion was that MSC augmentation may improve early mechanical properties in tendon repair and jump-start the repair process (34). Adams et al. studied the effects of suture alone, suture plus stem-cell-concentrate injection or stem cell-loaded suture in the repair of 108 rat Achilles tendon ruptures. At 14 days follow up the tendons from the subjects in the suture alone group had a lower failure load than the other two groups (33). Stein et al reviewed 27 patients with Achilles rupture who underwent open repair with BMAC augmentation. Mean follow up was 29.7±6.1 months. Ninety-two percent of patients returned to their sport at 5.9±1.8 months. There were no re-ruptures in the cohort (37).
Evidence suggests that both operative treatment modalities, reparative and regenerative techniques treating osteochondral lesions of the talus, demonstrate good to excellent short-term and mid-term clinical outcomes in up to 85% of cases (38). Nevertheless, the technical difficulty of the operative procedures and the inevitable deterioration of the regenerated or grafted cartilage are of concern (39 – 41). Previous studies propose that a combination of mechanical and biological impairments in the injured ankle joint may affect the deterioration, prompting interest in adjuvant modalities that could improve outcomes by addressing some of these deficits. Orthobiologic augmentation with BMAC may increase the longevity of cartilage repair when operatively treating osteochondral lesions of the talus. Its regenerative properties facilitate tissue healing; improve the quality of cartilage by increasing chondroitin sulfate proteoglycan and firmness of the repaired cartilage. BMAC also promotes the growth of hyaline cartilage and decreases the amount of fibrocartilage (4, 12-14). Although unapproved by the regulatory body, FDA, BMAC for chondral injury has yielded some promising results. Whether it is used for repair in osteoarthritis, osteochondral lesions or purely chondral lesions studies that support its use are becoming more widespread. Clinical applications of BMAC for cartilage repair consist of augmentation in microfracture, direct cartilage repair, and injections for osteoarthritis and post-traumatic arthritis. There is a paucity of long-term studies that solidify the use of BMAC augmentation in the treatment of OLTs (44). Clanton et al. reviewed the results of 7 patients at a mean follow-up of 8.4 months following arthroscopic treatment of OLTs with microfracture and a mixture of cartilage extracellular matrix augmented with BMAC. Activities and daily living subscale score and Foot and Ankle Disability Index scores both improved significantly at final follow up (43).
Fortier et al, in an equine knee comparative study, looked at the technique of microfracture with or without BMAC augmentation for the treatment of full-thickness cartilage defects. They reported improved defect filling, integration of repair tissue, collagen orientation, increased glycosaminoglycan and type II collagen content in the BMAC group. (4)
Increasing patient outcomes and returning them to there pre-injury state is of most importance for all foot and ankle surgeons. The use of BMAC for augmentation in bone, soft tissue and chondral repair shows promising results. There is, however, a great need for high level research to further analyze the positive efficacy BMAC on improved outcomes in healing pathologic conditions in the foot and ankle. There is little argument that harvesting BMA in the lower extremity is safe and cost-effective with no major complications reported.
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