Introduction

Serious orthopedic injuries such as non-unions and bimalleolar and pilon fractures, can be treated suc cessfully with the Ilizarov method [1]. However, complica tions to include contractures, pin track infections, loss of range of motion, and articular damage can occur. Patients, who are experiencing soft-tissue loss, comor bidities, and chronic infection, increase the complexity of these cases. Patients who are smokers of advanced age with a high rate of systemic illness are the most dif ficult to treat because these factors negatively impact the rate of healing and incidence of infection [2,3].

Therefore, the overarching challenge that surgeons face with these patients is to achieve a stable, well-aligned, mobile and pain-free joint while minimizing the risk of infection and post-traumatic osteoarthritis. The classic Ilizarov technique has several advantages when treating patients with various co-morbidities [4]. With this technique, the reduction and fixation of the fracture is performed with minimal soft-tissue exposure and blood loss and the fixation is stable enough to allow weight bearing soon after surgery. The external fixator affords the surgeon the opportunity to adjust the align ment, compression, and distraction during surgery and while the patient heals. Further, screws and plates are not left behind once the fracture is healed. Collectively, these factors improve the success rate of the Ilizarov method in fracture repair, and have a positive effect on patient quality of life [5].

In the treatment of complicated fractures, surgeons may also use an autologous iliac bone graft (ICBG) to augment healing potential. Specifically, autologous bone grafts possess the three key properties required for bone growth: osteogenic, osteoinductive and osteoconductive. Unfortunately, in patients with multiple comorbidities, autologous bone grafting may introduce new complications, particularly at the donor site. These include bleeding, infection, and chronic pain. More over, limited bone graft material is available which may not be sufficient for treatment [6]. Since the success of a bone graft is determined by the ability for the graft ed tissue to recruit progenitor cells to the injured area to form osteoblasts for healing purposes, alternative methods are needed in compromised patients.

Safe and effective alternative graft materials have become increasingly popular for use in patients with significant comorbidities. Demineralized bone matrix (DBM) is donor tissue that has been processed to re move inorganic mineral content, resulting in an organic collagen matrix [7]. As a result of this processing, DBM only retains minimal osteoinductive properties, high lighting the need for an additional material that can pro vide osteoprogenitor cells to improve the osteogeneic environment. One strategy is to aspirate the patient’s own bone marrow, remove red blood cells and con centrate osteoprogenitor cells in each volume of bone marrow harvested. The benefit of this is twofold: red blood cells can interfere with bone formation and heal ing [5] and concentrated osteoprogenitor cells increase the osteogeneic environment (Figures 1 & 2).

Consequently, the use of concentrated Bone Mar row Aspirate (cBMA) combined with an osteoinduc tive bone graft substitute (DBM) insures that two of the main properties for bone growth and healing are present with minimal risk and morbidity to the patient. Additionally, the use of Platelet Rich Plasma (PRP), a concentrated portion of a patient’s own blood, can aug ment the healing process since it introduces various growth factors and cytokines that can reduce infection and promote regenerative processes [8].

This case series retrospectively analyzes the safety and efficacy of combining DBM, cBMA, PRP, and the Ilizarov technique to promote fracture healing in a pop ulation of patients with complicated fractures and sig nificant comorbidities.

Materials and Methods

Patient Demographics

Thirteen patients (N=13) (N= 10 men and 3 women), mean age 52.9 years) with various comorbidities (di abetes, obesity, smoking, renal disease). All patients had closed bimalleolar (N=10), pilon (N=2), or distal tibia (N=1) fractures with a poor soft tissue envelope. Of the bimalleolar fractures, seven were AO Supination External Rotation (AOSER), and three were AO Prona tion External Rotation (AOPER). The pilon Fractures were AO classification Type 1 Ruedi and Allgower, re spectively. The distal tibia fracture was a Type 2 frac ture. Patients included in this case series received im plantation of cBMA, PRP, and DBM mixture along with Ilizarov fixation between January 2012 and December 2012. Patients were identified by a retrospective re view of physician office records.

As illustrated in Table 1, all patients had multiple co-morbidities including obesity (N=13); diabetes (N=12); smoking (N=8); osteoporosis (N=3), renal disease (N=3) and abnormal bone metabolic panels (Vitamin D and Calcium deficiency, N=10).

Bone Marrow Aspiration and Concentration

In all 13 procedures, 26 ml of bone marrow was har vested from the medial aspect of the proximal tibia (Figure 3A). First, the 30 ml syringe was primed with 4 ml of anticoagulant citrate dextrose solution (ACD-A) (Arteriocyte Medical Systems, Hopkinton, MA). A mal let was then used to advance the 15 gauge Jamshidi needle (Arteriocyte Medical Systems, Hopkinton, MA) until a decrease in resistance was met. The decreased resistance was used to indicate that the needle had en tered the marrow cavity. Bone marrow was then drawn back gently (to prevent lysing of the cells) into the 30 ml syringe that was primed with 4 ml of ACD-A. During the marrow draw, if significant resistance was met, the needle was repositioned until the marrow flowed eas ily. This prevented clotting and unnecessary physical disruption of the BMA, which can lyse cells and reduce growth factor content of the platelets. The needle was repositioned until a total volume of 30 ml, including the ACD-A, was harvested.

The harvested marrow was then filtered and processed in the Arteriocyte Magellan system (Arteriocyte Medical Systems, Inc., Hopkinton, MA) (Figure 3B). The Magel lan is an automatic, dual spin, closed system allow ing for safe and rapid bedside concentration of whole blood and bone marrow aspirate. For each case, the Magellan was customized to obtain a final volume of cBMA of approximately 3 ml from 30 ml of bone mar row aspirate.

For each patient, 30 ml of whole blood was drawn from an antecubital vein. First, the 30 ml syringe was primed with 4 ml of ACD-A and then 26 ml of whole blood was obtained from each patient using standard phlebotomy procedures. Once the final volume of 30 ml was ob tained, the syringe was loaded into the Magellan Sys tem. The Magellan was programmed to produce 3 ml of Platelet Rich Plasma (PRP) from the 30 ml volume (Figure 3B).

Demineralized Bone Matrix (DBM)

Integra Accell EVO, which is a DBM and poloxamer Reverse Phase Medium produced by Integra (Irvine, CA) was used in all patients. This form of DBM pro vides a high surface area, which facilitates binding ac cess for natural bone proteins, providing a scaffold and signal for new bone formation. The Accell EVO DBM is moldable putty at room temperature, which becomes more viscous at body temperature. Prior to use, the Accell EVO DBM was mixed with the cBMA to achieve desired consistency (Figure 3C & 3D). Five cc’s of DBM were injected into areas of non-union in patients with bimalleolar and distal tibia fractures. Ten cc’s of the Accell Evo DBM were used for pilon fractures (Fig ure 3E).

Ilizarov Technique

The circular fixator consisted of a pre-constructed frame that consisted of four rings (Figure 4). A proxi mal reference wire was fixed and tensioned to the most proximal ring. A distal reference wire was fixed directly proximal to the ankle. After the bone ends were fixed with opposing olive wires, radiology was used to as certain alignment of the bone. In cases where the non union was close to the ankle, the foot was incorporated into the frame to enhance stability and prevent equinus or varus contracture.

When the bones were properly aligned, the cBMA and Accell EVO DBM mixture were injected percutaneous ly using the 15-gauge bone marrow aspiration needle (Figure 3E). PRP and any remaining cBMA were in jected directly into the joint space. Viability of the foot was assessed via palpation of the dorsalis pedis and posterior tibial pulses, and measurement of oxygen saturation of the hallux. If circulation appeared to be disrupted, the length was adjusted as necessary to re turn circulation to normal. PRP combined with calcium chloride and thrombin solution, was applied using a spray-tip cannula at all wound sites to expedite healing (Figure 3F).

Results

Mean fixator time was 16 +1- 2 weeks. Post-operative radiographs for eleven of thirteen patients showed complete bone healing at the time that the external fixator was removed (approximately 4 months) (Figure 5). No infections were reported and no limbs were am putated in this series.

Patient 4 and Patient 7 experienced delayed closure. Patient 4 required a revision due to consistent pain. Four weeks post-revision, pain had subsided. Patient 7 had consistent pain post-procedure. A revision was performed with a percutaneous injection of cBMA. This patient was pain free within four weeks post-revision. Following revision, both patients healed within approxi mately four months without residual deformity or mor bidity.

Three patients experienced mild adverse reactions to include angulation of the fracture site (N=1) and super ficial irritation due to wires (N=2), which did not require antibiotics. Both pilon fractures had transient traction neuropathy of the superficial peroneal nerve.

Summary

The aim of the author’s strategy in combining the Il izarov technique with DBM, cBMA, and PRP was to de crease the period of external fixation, expedite fracture healing, and diminish the rate of complications, specifi cally infections. In this case series, complications that were reported were minor and only one required addi tional surgery. Excellent results were obtained in 11 of 13 patients and good results were obtained in the other two patients following additional interventions.

In summary, use of DBM, saturated with cBMA in combination with the Ilizarov technique results in an 85% healing rate in approximately four months. Addi tionally, PRP injected directly into the joint space pro motes healing. We conclude that the Ilizarov method combined with cBMA and PRP is a safe, reliable, and effective method with good clinical outcomes for the treatment of non-union fractures in patients with sig nificant comorbidities. The addition of cBMA resulted in a shorter treatment time and reduced complication rate. The addition of PRP, particularly to wound sites, reduced incidence of infection and promoted cutane ous tissue healing.

1. Krappinger D, Irenberger A, Zegg M, Huber B (2013) Treatment of large posttraumatic tibial bone defects using the Ilizarov method: a subjective outcome assessment. Arch Orthop Trauma Surg 133(6): 789-795.
2. Blum AL, BongioVanni JC, Morgan SJ, Flied MA, dos Reis FB (2010) Complications associated with distraction osteogenesis for infected nonunion of the femoral shaft in the presence of a bone defect: a retrospective series. J Bone Joint Surg Br 92(4): 565-570.
3. Sella EJ (2008) Prevention and management of complications of the Ilizarov treatment method. Foot Ankle Spec 1(2):105-107.
4. Ramos T, Karlsson J, Eriksson BI, Nistor L (2013) Treatment of distal tibial fractures with the Ilizarov external fixator--a prospective observational study in 39 consecutive patients. BMC Musculoskelet Disord 14: 30.
5. Brinker MR, O'Connor DP (2007) Outcomes of tibial nonunion in older adults following treatment using the Ilizarov method. J Orthop Trauma 21(9): 634-642.
6. Pieske O, Wittmann A, Zaspel J, Löffler T, Rubenbauer B, et al. (2009) Autologous bone graft versus demineralized bone matrix in internal fixation of ununited long bones. J Trauma Manag Outcomes 3: 11.
7. Gruskin E, Doll BA, Futrell FW, Schmitz JP, Hollinger JO (2012) Demineralized bone matrix in bone repair: history and use. Adv Drug Deliv Rev 64(12): 1063-1077.
8. Guo Y, Qiu J, Zhang C (2008) Follow-up study on platelet-rich plasma in repairing chronic wound nonunion of lower limbs in 47 cases. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 22(11): 1301-1305.

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  Figure 1: Cellular content of bone marrow.

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  Figure 2: Cellular component of bone marrow with RBC fraction re¬moved. (MSC- mesenchymal stem cell, HSC- hematopoietic stem cell, MNC- mononuclear cell, TNC- total nucleated cells).

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  Figure 3: A. Bone marrow aspiration method. B. Magellan Platelet Separator. C. Syringe containing initial mixture of cBMA and DBM. D. Final implantable mixture of cBMA and DBM. E. Application of cBMA and graft material to fracture site. F. Application of PRP using a spray tip cannula.

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  Figure 4: Ilizarov method of fixation.

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  Figure 5: A. Pre-treatment radiograph of a female patient with a bi¬malleolar fracture (yellow arrow), B. Fluoroscopy image of olive wire stabilization of the fracture. C. Post- treatment radiographs of same female patient at 16 weeks post-procedure. Fracture is healed (yellow arrow).

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  Table 1: Patient Demographics