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First in Man: Sternal Reconstruction with Autologous Stem Cells Zain Khalpey .1' Katherine M. Marsh,* Alice Femg,* lrbaz Bin Riazit Courtney Hemphill,* Kitsic Johnson,* Isabel Ohs a4 and Mark Friedman§ Acknowledgment The authors acknowledge IntelliCell BioSciences and Dr. Steven Victor, MD for implementation of the SVF isolation protocol using ultrasonic cavitation. The authors thank Synthes who helped 3D print the diseased sternum for preoperative surgical planning. EFTA01193379  Last eepu-:, ASAIOlournal 2015 First in Man: Sternal Reconstruction with Autologous Stem Cells ZAN KHALPEV,• KATHERINE M. MARCH,* ALICE IRBAE 61. RW,t C(%RTNEY I IMPHILL,* KITSIE JOHNSON,' ISABEL OLIVA,$ AND MARK filiE0wAs§ Sternal nonunion is associated with high morbidity and treated the past decade. Their potential as progenitor/stem cells has been using rigid plate and screw fixation. This is the first reported shown to be equivalent to the properties of pluripotent stem cells example of successful sternal reconstruction using adipose- or oven advantageous to using other populations of stern cells due derived stromal vascular fraction (SW) stem cells in addition to their low immunogenicityl These cells can be readily isolated to traditional techniques. Mesendwrnal stem cells, one com- via noninvasive lipoaspiration from subcutaneous fat at a much ponent of the SW, play an important role in bone healing and higher yield than other sources, and has since e,nerged as an alter- were therefore used to promote remedial processes in a patient native tissue source for use in regenerative medicine. These ad-- with sternal nonunion. A 3D printed model of the patient's ster- pose-tissue SW cells, or adipose-derived stem cells (ASCs, have num was used for preoperative planning of the plating. Intra- been used in studies that include cartilage and hone regeneration, operatively, SVF was isolated using ultrasonic cavitation and wound healing, articular cartilage defaces, and tissue regeneration. previously planned sternal plating was completed. A total of Because SVF cells can be used without expansion and cell-culture 300 million cells were delivered via both local injection and treatment, the stem cells undergo minimal manipulation before intravenously before chest closure. The patient's pain dramati- clinical use. Though in vitro expansion also sham that human cally decreased, commensurate with healed areas of nonunion MSCs do not seem to undergo malignant transformation. SW cells by 3 months and maintained at 6 months postoperatively, are even more sale and efficacious due to the minimal manipu- supported by three-dimensional computed tomography imag- lation! Other studies show further evidence that there are yan- ing. Utilizing autologous stem cells from the SVF in conjunc- ks components of crude SVF that act synergistically with ASCs, tion with existing plating techniques may provide an optimal which may be non' clinically beneficial than ASCs alone.' Adi- platform to stabilize the sternum and promote bone healing, pose-cierised stem cells are also more immurtosuppresshe than although additional study is recommended. ASAIO Journal bone marrow-derised stern cells, another common source used in 2015; 61:e31-e32. preclinical and clinical studies/ There are many current, ongoing clinical trials invoking the use of autologous adipose tissue SW Key Mnrds: sternal reconstruction, autologous stem cells, cells for various disease etiologies including osteoarthritis, spinal human adipose-derived stem cells, hADSCs, adipose-derived cord injury, multiple sclerosis, and acute msdardial infarction!' stromal vascular stein cells, MC Although there is always a possibility of side effects from the deliv- ery cistern cells, minimal side effects are expected from SVF MSCs compared with other cell types, because ,v6Cs have been shown S ternal nonunion, although rare, is associated with high mor- to modulate 1-cell-mediated immunological responses.' Methods bidity) Various fixation techniques have been described with the ultimate goal of rigid fixation and bony union to promote bone of delivery include both intravenous injection and local injection. healing) Natural bone healing involves many pincemes includ- both of which have been shown to cause cell homing to the sited ing stern cell involvement. Research has highlighted the important ischemia or injury? Here. aye outline the first reported case of successful sternal role of mesenchsmal stem cells IMSCs) in bone repair, which has reconstruction with autologous stem cells from the WE. Utiliz- lead to the exploration of additional therapeutic options.' Emerg- ing treatments include the use of adipose-derhed stromal vascular ing this accessible heterogeneous mixture of cells in conjunc- tion with existing plating techniques may provide an optimal fraction lsvn cells, which contain multi-potent CD3 I +, CD34+, platform to stabilize the sternum and promote bone healing. CD-14+, C090., a)73+. and CO105+ cells characteristic of MSCs, in addition to exhibiting mesodermal capacity.' Stromal vascular fraction cells have been studied extensively in vitro over Case Report A 65 sear old male presented with disabling pleuritic chest pain due to chronic sternal nonunion with bone loss after coro- from the 'Division of Cardiothoracic Surgery, Department of Sur. b)ers: iDepartment of internal Medicine. 'Department of It-Ashok.% nary artery bypass grafting. This began following an episode of and §INvision of Cardiology, Department of Internal medicine, Flannel- severe coughing secondary to upper respiratory tract infection. University medical center, luoon, Arizona. Three-dimensional computed tomography of the chest (3D CT) Submitted for consideration August 2014: accepted tor publication showed a comminuted lower sternal fracture and nondisplared in revised form December 2014. healing fractures of the left fifth and right fifth and sixth ribs. Disclosure The authors have no conflicts of interest ro report. Supported by the University of Arizona medical Center and College Although the wired upper portion of the sternum remained intact, of medicine, Department of Surgery. the lower sternum had fractured in three places and distracted orrespondence Zain Khaipey, 1501 N. carnpbell Ave, fon 4.302A into four principal pieces greater than 5cm apart figure 1A). Amer li Box 245071 Tucson. AZ 85724.5071. Email: zkhalpeyesurgery. anion«du. Copyright O 2015 k the Anx-fican Society for Artificial Internal medical therapy proved unsuccessful, a sternal reconstruction and unilateral pectoralis flap reconstruction was recommended. (Jegant Given the extensive sternal nonunion, we constructed a preoped- DOI: 10.1097/MAT.0000000000000236 tive 3D printed image of the patients sternum augmented with e31 Copyright American Society of Artificial Internal Organs Unauthorized reproduction of this article is prohibited. EFTA01193380  nonunion are indicated by arrows Figure 1. Three-Ornersgonal corr.outeci tomography image. Fracture sites and regions of sternal (AL and healed fractures are indicated by avows at 3 months (B) and 9 months postoperatively (C)- preoperatively biomaterials and mock-prepared the joints and the plating sys- including osteoarthritis and spinal cord injury.' ' In addition, tem (Synthes, DePuy, Ws) Chester, l'A). This was completed to the usefulness of ASCs in various mound and bone healing both plan and practice the procedure in three dimensions before applications has been studied in multiple animal models with surgery. Although in vitro stem cell injection was not completed evidence that they promote the type of accelerated regenera- during the planning phase, after completion of the plating, we tion we have seen in our patient.' Due to the ability to eas- identified potential locations for local stem cell injection. ily acquire both autologous stem cells ladipose-derived and Intraoperatively, we performed sternal plating with bone putty stromal vascular progenitor cells? and native micromatrix from as planned preoperatively, and harvested autologous adipose- liposuction-derived adipose tissue in the operating roan, our derived WE stem cells with ultrasonic cavitation unfelt'Cell Bio- method of SW isolation and application make this an attractive sciences, New York, NY). A sterile section of the operating room therapeutic option. The engraftment of the SVF and generation (OR) was used for the WE isolation procedure, which included of stable bone highlights the importance of cell-matrix com- a centrifuge, flow atometer, sonicator probe, and the neces- bination therapy options, rather than stem cell therapy alone. sary accessories. Before the plating procedure, lipoaspirate was This has implications for cardiac and orthopedic regeneration. obtained via standard liposuction from the patients abdomen. The WE isolation procedure was immediately' implemented using the lipoaspirate and completed 1 hour later, by the time Acknowledgment the surgeon had completed the sternal reconstruction. This The authors acknowledge IntelliCell RioSciences and Dr. Steven Vic- allowed for prompt injection of the freshly isolated, autologous tor, MD for implementation of the SW isolation protocol using ultra- SVF cells: 100 million via localized injection and ?CO million sonic cavitation. The authors thank synths,% who helped 3D print the eta intravenous injection. The SVF was a heterogeneous popula- diseased sternum for preoperative surgical planning. tion of cells and extracellular matrix that can be used clinically without expansion.' and was mostly composed of CD34+ cells References with approximately 88% cell viability. finally, a unilateral pec- 1. Chepla K1, Salgado Cl, Tang CI. Mardini S, Fvans 10<: late com- loralis flap reconstruction was completed before closure. plications of chest wall reconstruction: Management of painful Serial 3D CT imaging demonstrated fracture healing and sternal nonunion. Semis Plait Sorg 25: 98-106, 2011. closure of areas of nonunion 3 and 6 months postoperatively 2. Scrioga M. Viswanathan 5, Darinskas A, Slaby 0. Michalek 1: Same compared with preoperative imaging figure 1B, C). Since sue or not the same? Comparison of adipose tissue-derived versus bone 'narrow-derived mesenchymal gem and stromal cells. gery, the patient has established regular follow up at our out- Stern ret7s 13ev 21: 2724-2752. 2012. patient facility. His sternum is stabilized and he now reports 3. Khalpey L, lanardhanan R. Konhilas 1, Hemphill C: First in 111411: minimal to no pain, with normal exercise tolerance. This case Admose-derned stromal vascular fraction cells may promote is the first reported example in man of successful sternal recon- restorative cardiac function. Am/ .leer/ 127: ell -e12, 2014. struction with adipose-derived SVE 4. Translational Rictsciences. Safety and feasibility study of autologous stromal vascular fraction 'SW, cells for treatment of osteoarthri- tis. In: ClinicatTrials.gov :Internet]. National Lbrary of Medicine Discussion (US). June 2013. Available at httpsYclinicaltrialsgov/show/ WM1885832. Accessed October 19th, 2014. Medial sternontomies are the gold standard for many car- 3. Yagi H, Soto-Gutierrez A, Parekkadan 8, et al: Mesenchymal stem diothoracic surgical procedures. Sternal nonunion occurs in cells: Mechanisms of immunomodularicin and homing. Cell approximately 0.5-3% of all patients with standard wire fixa- transplant 19: 667-679, 2010. tion, with greater risk in patients who are on prolonged ven- 6. I lannoush El. Sail ZC. Flhassan lo, err 4: Impact of enhanced tilation, female, older age, or overweight.. Treatment options mobilization of bone marrow derived cells to site of injury. have included repeat circumferential peristernal rem iring, steel I Trauma 71: 283-9; discussion 289, 2011. 7. Demme O, .Moisan A, Dimastromageo I. et al: Intravenous admin- banding, polymer tapes, and absorbable sutures. but currently istration of 99mTc-I IMPAO.labeled human mesenchyrnal stem rigid plate and screw fixation is most widely utilized.' cells after stroke In vivo imaging and biodistribution. Cell Despite improvements in fixation technologies and alio- Trantplani 18: 1349-1379, 2009. geneic bone matrices, there is no guarantee that healing will 8. Climble km, Bunnell BA. Chiu ES, GuiLak F: Concise review: occur. As mentioned earlier, hunun AM(: transplantation has Adipose-derived stromal vascular fraction cells and stern cells: shown promise in current orthopedic-related clinical studies. Let's not get lost in translation. Stem cas 29: 749-754, 2011. prohibited. Copyright © American Society of Artificial Internal Organs Unauthorized reproduction of this article is EFTA01193381 ASAIO I O U R N A L EFTA01193382