Case Report
Mesenchymal Stem Cell Allograft in a Nonunion Fibular Fracture: A Case Report
Brett D Sachs1* and Kaitlyn Bernhard2
1Departemnt of Podiatric Surgery, Presbyterian St. Luke’s Medical Center, USA
2Deprtment of Podiatric Medicine and Surgery, Presbyterian St. Luke’s Medical Center, USA
*Corresponding author: Brett D Sachs, Highlands-Presbyterian St. Luke’s Podiatric Medicine and Surgery Program, Presbyterian St. Luke’s Medical Center, Wheat Ridge, 80333, CO, USA
Published: 31 Mar, 2017
Cite this article as: Sachs BD, Bernhard K. Mesenchymal
Stem Cell Allograft in a Nonunion
Fibular Fracture: A Case Report. Clin
Surg. 2017; 2: 1395.
Abstract
Ankle fractures are common injuries treated by the foot and ankle surgeon. The majority of stable, uncomplicated, minimally or non-displaced distal fibular fractures will heal with adequate immobilization and conservative treatment. However, some patients will develop a symptomatic partial union or nonunion. Several factors can contribute to a nonunion following a fracture including smoking, obesity, infection, and diabetes mellitus. In cases of surgical reconstruction, augmentation with osteobiologics consisting of mesenchymal stem cells can be utilized to enhance osseous healing of the nonunion site. We present a successful case of a distal fibular nonunion repair with the use of a partially demineralized allograft bone combined with adipose derived mesenchymal stem cells to promote bone healing. At six months follow-up, there was solid bone healing of the fibular nonunion with complete resolution of symptoms.
Introduction
Ankle fractures are an increasingly common injury to the ankle joint. The incidence of ankle
fractures is approximately 187 fractures per 100,000 people per year [1]. Ankle fractures in general
occur from a rotation force on the ankle with the most typical mechanism related to a fall from a
height or stairs [2]. Other etiologies include sport activity, blunt trauma, and motor vehicle accident.
The most common fracture is the lateral malleolus followed by bimalleolar, trimalleolar and isolated
medial malleolar fractures [2-4]. The two common classification systems used for ankle fractures
are the Lauge-Hansen and Danis-Weber classifications. The Lauge-Hansen system is based on
the position of the foot and the direction of the force at the time of injury [5]. The supinationexternal
rotation mechanism is the most common type of ankle fracture [6,7]. The Danis-Weber
classification is based on the level of the fibular fracture to the ankle joint [8]. In the average patient,
the standard treatment for displaced ankle fractures is open reduction with internal fixation [9].
A nonunion following a fracture can present a difficult challenge for the foot and ankle surgeon.
The incidence of a fibula nonunion is 0.3% to 5.4% [10]. A successful union can be influenced by
several risks factors that are associated with poor bone healing including smoking, osteoporosis,
diabetes mellitus, obesity, steroid use, advanced age, nutritional deficits, alcohol, vitamin D
deficiency, thyroid disorders, and nonsteroidal anti-inflammatory drugs [11,12]. These factors can
also affect ankle fracture healing [13-17]. There have been numerous prognostic factors associated
with a ibular nonunion following fracture including fracture displacement, oblique fracture
pattern, degree of bone loss and fracture combination, and high-energy injuries. A nonunion
is typically classified as either a hypertrophic or atrophic nonunion according to the vascularity
and amount of bone callus formation present on plain radiographs [10]. A nonunion of the distal
fibula is considered relatively rare due to the adequate blood supply and minimal biomechanical
stress during ambulation. The treatment of the distal fibular nonunion is generally based on the
symptoms, fracture characteristics, and type of nonunion [10].
Bone grafts have been utilized for a variety of foot and ankle procedures. Bone grafts can provide
structural support, fill a void or bone deficit, and enhance bone healing. The biological principles
of bone graft healing include osteoconduction, osteoinduction and osteogenesis. Since autogenous
bone grafts possess all three properties, they have historically been the gold standard for the use in
nonunion repair for many years. However, harvesting of an autogenous bone graft can result in
complications such as donor site morbidity, pain, fracture, seroma and infection [18]. Surgeons have
been employing allogenic bone grafts with mesenchymal stem cells (MSCs) in an effort to acquire
a more predictable alternative for grafting material. MSCs are precursor cells that have the capacity to differentiate and proliferate into multiple cell lines. Several studies
have demonstrated that augmentation with MSCs implemented as a
cellular bone matrix is a beneficial adjunct for bone healing [19-23].
We describe a case of a patient that developed a distal fibular
nonunion following conservative treatment. Osseous union required
operative treatment consisting of resection of the nonunion,
internal fixation for stabilization, and use of AlloStem® (AlloSource®,
Centennial, CO, USA) to facilitate bone healing. AlloStem® bone
graft is a combination of partially demineralized cancellous bone and
MSCs, which are harvested from donor cadaveric abdomen adipose
tissue.
Figure 1
Figure 2
Figure 3
Figure 3
Final 12 weeks postoperative radiographs depicting complete
osseous healing of the fibular nonunion.
Figure 4
Case Presentation
We present a case of a 46-year-old male who sustained a left distal fibular fracture in January 2014. He recalls walking on uneven
ground, felt his ankle “twist”, and collapsed to the ground. The patient
described an inversion-type ankle injury and immediately experienced
pain and swelling to the left lateral ankle area. He initially treated the
area with rest and elevation. However due to the lack improvement
in the symptoms, the patient went to an emergency department a
few days later where radiographs demonstrated a SER-type II ankle
fracture. A cam boot walker and crutches were dispensed along with
instructions to be non-weight bearing to the injured ankle. He was
referred to another physician who treated the injury conservatively
for approximately 3 months. The patient worked as a mechanic and admitted to weight bearing in the cam boot walker soon after the
initial injury. A magnetic resonance imaging study was obtained in
June 2014, showing limited osseous formation without solid fusion
of the oblique fibular fracture. In addition, a Computed Tomography
(CT) scan performed in July 2014 revealed incomplete osseous
bridging and evidence of osteopenia (Figure 1).
After six months of persistent pain of the left lateral ankle, the
patient presented to the author’s clinic in August 2014 for a second
opinion. The patient was concerned that his left ankle fracture never
healed properly. He had a medical history of hypertension, thyroid
disease, heart murmur, and obesity. His medications included
tramadol, trazodone, baclofen and losartan. Past surgical history
included hernia repair. The patient had no known drug allergies. In
addition, he is a current smoker with a 30-pack year smoking history.
The patient denied any alcohol or illicit drug use.
On physical exam, his lower extremity neurovascular status was
within normal limits. There was moderate pain upon palpation of
the left lateral ankle area with minimal edema present. There was no
evidence of ankle instability and the ankle syndesmosis appeared to
be intact. Plain film radiographs revealed minimal osseous healing of
the distal fibula fracture (Figure 2). Due to the persistent pain of the
fibular nonunion, we recommended surgical treatment consisting of
repair and stabilization of the nonunion with internal fixation, ankle
arthroscopy, and application of bone graft. We also recommended
smoking cessation, however he continued to smoke throughout the
peri operative course. In addition, preoperative labs were obtained
including 25-hydroxyvitamin D, ionized calcium, and parathyroid
hormone levels. An external bone stimulator was also recommended,
however the insurance carrier did not approve the device. The
calcium and parathyroid hormone levels were within normal limits.
However, the 25-hydroxyvitamin D was relatively low at 32 ng/mL.
The patient was subsequently treated with vitamin D 2,000 IU daily
and was advised to continue this supplementation until evidence of
union.
The patient underwent repair of the distal fibular nonunion with
general anesthesia and popliteal nerve block. Ankle arthroscopy
was initially employed to evaluate the joint and remove any
synovitis present. The articular cartilage appeared normal without
osteochondral lesions visualized. Attention was then directed to the
nonunion fibular fracture, where a standard longitudinal incision
was made overlying the distal fibula. The nonunion was easily
identified. The distal fragment was unstable with fibrous tissue noted
throughout the nonunion site. There was no osseous healing present.
The nonunion was excised and all necrotic tissue was completely
debrided to the level of bleeding bone. The defect was also fenestrated
with a 2.0 mm drill to promote bleeding across the site. At that time,
the AlloStem® bone graft was positioned across the previous fracture
site. Utilizing lag technique, a 3.5 mm cortical bone screw was placed
across the fracture site with excellent compression noted. Next, a
lateral plate (Peri-Loc VLP®, Smith & Nephew, Memphis, TN) was
applied with 3.5 mm locking screws as neutralization construct for
additional stability. The construct was stressed under fluoroscopy
and was noted to be stable. The incisions were irrigated and closed
in layers in standard technique. The patient was placed in a posterior
splint.
Post-operatively, the patient was instructed to remain nonweight
bearing on the operative lower extremity. He was to remain
non-weight bearing until radiographic signs of union were present.
At two weeks, he was placed in a below the knee fiberglass cast.
Subsequently at three weeks, the patient decided to bi-valve his
cast in order to bathe. In addition, he refused application of a new
cast at this time. The patient periodically reapplied the bi-valve cast
with Velcro straps. The vitamin D level was repeated at three weeks
demonstrating a decrease to 31 ng/mL suggesting a non-compliance
with the prescribed supplementation. Plain film radiographs
were obtained at approximately four weeks, which revealed some
evidence of trabeculation across the fibular nonunion. During the
post-operative period, the patient remained non-compliant. The
patient had missed several appointments and continued to smoke.
Since the external bone stimulator was denied by his insurance, the
patient opted to create a home made stimulator from a TENS unit.
At twelve weeks following the procedure, radiographs revealed
evidence of complete osseous union of the previous fibular nonunion
(Figure 3). The patient was transitioned to protected weight bearing
in a pneumatic cam walker boot. A repeat CT scan was ordered at
four months to ensure healing of the operative site (Figure 4). The
CT scan revealed 90% osseous union without evidence of hardware
complications. The patient was therefore progressed into normal
shoe gear. The patient experienced complete resolution of symptoms
and was able to ambulate without limitation.
Discussion
The treatment of acute ankle fractures is well reported in the
literature. There are numerous documented etiologies of nonunion
following fractures including smoking, osteoporosis, diabetes
mellitus, obesity, steroid use, advanced age, nutritional deficits,
alcohol, vitamin D deficiency, thyroid disorders, and nonsteroidal
anti-inflammatory drugs [11,12]. The detrimental effects of smoking
on bone and wound healing have been well documented in the
literature. Although cigarette smoke has several compounds, the
carbon monoxide, nicotine, and hydrogen cyanide are the chemicals
that have been implicated in the impairment of bone healing [24,25].
In 2009, Krannitz and colleagues [25] evaluated 46 patients following
an elective bunionectomy procedure. The patients in the study
were divided into 3 groups including smokers, nonsmokers, and
secondhand smokers. The mean time to osseous healing was 69 days
in nonsmokers, 120 days in smokers, and 78 days in secondhand
smokers. This equates to 42% increase bone healing time in smokers.
Cobb “et al.” [26] reported a 3.75 to 16 times greater risk of nonunion
with an ankle arthrodesis in smokers as compared to nonsmokers.
Vitamin D is critical for ideal bone growth and health. Vitamin D
deficiency has been associated to poor bone healing, osteoporosis and
osteomalacia [27]. In 2010, Bogunovic and colleagues [28] studied
723 patients that had planned orthopedic surgery. They noted that
43% of the patients had insufficient serum vitamin D levels. In
addition, Smith “et al.” [29] studied 75 patients with foot and ankle
fractures. They reported that the vitamin D levels in 47% of patients
were below 30 ng/mL and 13% of patients were below 20ng/mL. The
authors concluded that vitamin D monitoring and supplementation
should be considered in patients with fractures. The patient in our
case study had a documented history of smoking and relatively low
vitamin D, which we believe contributed to the nonunion.
The use of osteobiologics has become increasingly popular in foot
and ankle surgery specifically in the high-risk patient or reconstructive
surgical procedures. Although the autograft has become the reference
standard, there are limitations and potential complications that may
restrict its use in foot and ankle surgery [18,30]. There are numerous biologic alternatives that exist including allogenic bone, bone morphogenic protein, bone marrow aspirate, demineralized bone
matrix, and Mesenchymal Stem Cell (MSC) allograft. MSC allografts
have recently been studied in the literature with promising results. In
2014, Anderson and colleagues [19] studied 85 patients with ankle
fusions that received either MSC bone allograft or proximal tibia
autograft. In the MSC allograft group, 84.1% achieved radiographic
fusions in a mean interval of 13.0 weeks. In another study, Scott
“et al.” [22] evaluated 20 patients with high-risk foot and ankle
reconstructions that were augmented with a MSC allograft. They
reported a 100% fusion rate with a mean average interval to fusion in
11.6 weeks. Thirty-five percent of these patients admitted to tobacco
use. Rush “et al.” [21] reported a 91.3% union rate in 23 patients in
revision foot and ankle surgery utilizing a MSC allograft. The study
noted an overall median time to union of 72.5 days. Interestingly,
they also reported a median time to fusion for patients without
diabetes mellitus of 66.5 days and a median time to fusion for patients
with diabetes mellitus of 91 days. Several studies have shown that
adipose derived and bone marrow derived MSCs are effective in bone
formation and healing [31-34]. Cellular allografts containing MSCs
can be an effective adjunct to enhance osseous healing in foot and
ankle arthrodesis and reconstructive procedures. In addition, the
MSC allograft is a feasible option in the high-risk patient population.
Conclusion
A nonunion following an ankle fracture can be a devastating deformity. Several factors have been associated to inadequate bone healing and nonunion. The MSC allograft can be a useful adjunct to facilitate bone healing in a nonunion. Allografts containing MSCs can promote osseous healing through the three key principles of osteoconduction, osteoinduction, and osteogenesis. Despite several compounding factors for potential nonunion and the challenges during the post-operative period in this particular patient, the MSC allograft was an excellent choice to promote bone healing. Allografts with MSCs are a reasonable option for foot and ankle surgery.
References
- Daly PJ, Fitzgerald RH, Melton LJ, Ilstrup DM. Epidemiology of ankle fractures in Rochester. Minnesota. Acta Orthop Scand. 1987;58(5):539-44.
- Jensen SL, Andresen BK, Mencke S, Nielsen PT. Epidemiology of ankle fractures. A prospective population-based study of 212 cases in Aalborg, Denmark. Acta Orthop Scand. 1998;69(1):48-50.
- Court-Brown CM, McBirnie J, Wilson G. Adult ankle fractures-an increasing problem? Acta Orthop Scand. 1998;69(1):43-7.
- Hasselman CT, Vogt MT, Stone KL, Cauley JA, Conti SF. Foot and ankle fractures in elderly white women: incidence and risk factors. J Bone Joint Surg Am. 2003;85(5):820-4.
- Lauge-Hansen N. Fractures of the ankle II. Combined experimental-surgical and experimental-roentgenologic investigations. Arch Surg. 1950;60(5):957-85.
- Singh R, Kamal T, Roulohamin N, Maoharan G, Ahmed B, Theobald P. Ankle fractures: a literature review of current treatment methods. O J Ortho. 2014;4(11): 292-303.
- Tikwani NC, Park JH, Egol KA. Supination external rotation ankle fractures: A simpler pattern with better outcomes. Indian J Orthop. 2015;49(2):219-22.
- Weber BG. Die Verletzungen des Oberen Sprungelenkes. Bern, Verlag Hans Huber, 1972.
- Guman G. Ankle fractures. In: Fractures of the Foot and Ankle. 2004; 265-334.
- Bhadra AK, Roberts CS, Giannoudis PV. Nonunion of fibula: a systematic review. Int Orthop. 2012;36(9):1757-65.
- Calori GM, Albiseti W, Agus A, Iori S. Tagliabue L. Risk factors contributing to fracturenonunions. Injury. 2007;38(2):11-18.
- Thevendran G, Younger A, Pinney S. Current concepts review: risk factors for nonunions in foot and ankle arthrodesis. Foot Ankle Int. 2012;33(11):1031-40.
- Dodson NB, Ross AJ, Mendicino RW, Catanzariti AR. Factors affecting healing of ankle fractures. J Foot Ankle Surg. 2013;52(1):2-5.
- Egol KA, Tejwani NC, Walsh MG. Eapla, Koval DJ. Predictors of short-term functional outcome following ankle fracture surgery. J Bone Joint Surg. 2006;88(5):974-9.
- Jones KB, Maiers-Yelden KA, Marsh JL, Zimmerman MB, Estin M, Saltzman CL. Ankle fractures in patients with diabetes mellitus. J Bone Joint Surg Br. 2005;87(4):489-95.
- Schuit S, van derKlift M, Weel A, de Late C, Burger H, Seeman E, et al. Fracture incidence and association with bone mineral density is elderly men and women: the Rotterdam Study. Bone. 2004;34(1):195-202.
- Strauss EJ, Frank JB, Walsh M, Koval KJ, Egol KA. Does obesity influence the outcome after the operative treatment of ankle fractures? J Bone Joint Surg Br. 2007;89(6):794-8.
- Boone DW. Complications of iliac crest graft and bone grafting alternatives in foot and ankle surgery. Foot Ankle Clin. 2003;8(1):1-14.
- Anderson JJ, Boone JJ, Hansen M, Brady C, Gough A, Swayzee Z. Ankle arthrodesis fusion rates for mesenchymal stem cell bone allograft versus proximal tibia autograft. J Foot Ankle Surg. 2014;53(6):683-6.
- Arinzeh TL. Mesenchymal stem cells for bone repair: preclinical studies and potential orthopedic applications. Foot Ankle Clin. 2005;10(4):651-5.
- Rush SM, Hamilton GA, Ackerson LM. Mesenchymal stem cell allograft in revision foot and ankle surgery: a clinical and radiographic analysis. J Foot Ankle Surg. 2009;48(2):163-9.
- Scott RT, Hyer CF. Role of cellular allograft containing mesenchymal stem cells in high-risk foot and ankle reconstruction. J Foot Ankle Surg. 2013;52(1):32-5.
- Skovrlj B, Guzman JZ, Maaieh MA, Cho SK, Iatridis JC, Qureshi SA. Cellular bone matrices: viable stem cell-containing bone graft substitutes. Spine J. 2014;14(11):2763-72.
- Haverstock BD, Mandracchia VJ. Cigarette smoking and bone healing: implications in foot and ankle surgery. J Foot Ankle Surg. 1998;37(1):69-74.
- Krannitz KW, Fong HW, Fallat LM, Kish J. The effect of cigarette smoking on radiographic bone healing after elective foot surgery. J Foot Ankle Surg. 2009;48(5):525-7.
- Cobb TK, Gabrielson TA, Campbell DC, Wallrichs SL, Ilstrum DM. Cigarette smoking and nonunion after ankle arthrodesis. Foot Ankle Int. 1994;15(2):64-7.
- Holick MF. Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J Clin Nutr. 2004;80(6):1678-88.
- Bogunovic L, Kim AD, Beamer BS, Nguyen J, Lane JM. Hypovitaminosis D in patients scheduled to undergo orthopedic surgery: a single-center analysis. J Bone Joint Surg Am. 2010;92(13):2300-4.
- Smith JT, Halim K, Palms DA, Okike K, Bluman EM, Chiodo CP. Prevalence of vitamin D deficiency in patients with foot and ankle injuries. Foot Ankle Int. 2014;35(1):8-13.
- Chiodo CP, Hahne J, Wilson MG, Glowacki J. Histological differences in iliac and tibial bone graft. Foot Ankle Int. 2010;31(5):418-22.
- Ehrhart NP, Chubb L, Flaumenhaft E, Barret C, Shi Y. Influence of adipose-derived mesenchymal stromal cell demineralized bone composite on new bone formation in critical sized cortical bone defects. Med Res Arch. 2015;1:1-14.
- Kang BJ, Ryun HH, Park SS, koyama Y, kikuchi M, Woo HM, et al. Comparing The Osteogenic Potential Of Canine Mesenchymal Stem Cells Derived From Adipose Tissues, Bone Marrow, Umbilical Cord Blood, And Wharton's Jelly For Treating Bone Defects. J Vet Sci. 2012;13(3):299-310.
- Li CY, Wu XY, Tong JB, Yang XX, Zhao JL, Zheng QF, et al. Comparative analysis of human mesenchymal stem cells from bone marrow and adipose tissue under xeno-free conditions for cell therapy. Stem Cell Res Ther. 2015;6(1):1-13.
- Wen Y, Jiang B, Cui J, Li G, Yu M, Wang F, et al. Superior osteogenic capacity of different mesenchymal stem cells for bone tissue engineering. Oral surg oral med oral pathol oral radiol. 2013;116(5):324-32.