theuse objectives ofadult mesenchymal stemcells ... cme.pdf · stemcells asdescribed above,mesenchy...

can differentiate into one, two, ormany cell types. In essence, theadult mesenchymal stem cell is mul-tipotent. They can differentiate intovarious types of tissues including,but not limited to bone, cartilage,adipose, and endothelium cells. Asthe embryonic stem cells developinto adult stem cells, they lose theirtotipotential ability, but increasetheir specialization. In 1924, Alexan-

Continued on page 212

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mal stem cells are completely dif-ferent than the controversial em-bryonic stem cell. Embryonic stemcells result from the egg and spermat conception. They are totipoten-tial, which means that they havethe capacity to grow into any celltype without exception. The adultstem cell has limited potential fordifferentiation compared to theembryonic stem cell.

Adult mesenchymal stem cells

By Howard Kimmel, DPM

Stem cells by definition are pri-mal undifferentiated cells thatcan differentiate into multiple

cell types. The body has a reservoirof these cells in various tissues.Adult stem cell therapy is an evolv-ing exciting therapy in medicine.Adult stems cells play a significantrole in the daily maintenance ofthe body. These adult mesenchy-

Objectives1) To know the dif-

ferences betweenadult mesenchymalstem cells and em-bryonic stem cells.

2) To understandhow adult mesenchy-mal stem cells aredistinguished andhow they are activat-ed to form varioustypes of tissue.

3) To be able tounderstand all theclinical applicationsof adult mesenchy-mal stem cells.

Continuing

Medical Education

The Useof AdultMesenchymalStem Cellsin ReconstructiveFoot SurgeryRecent research shows great promise for the useof these cells.

press the immune response and in-hibit the T and B cell-mediated de-struction of the injury site.6

First, mesenchymal stem cells atthe repair site proliferate to generatea substantial number of new mes-enchymal stem cells. Various factorscontrol this process. The mesenchy-mal stem cells at the repair site arethen committed and enter a specificlineage pathway, i.e., bone. For amesenchymal stem cell to turn intobone, a bone morphogenetic proteinsignals this differentiation. Oncethese cells are committed along thispathway, they continue to undergothese distinctive changes. This pro-cess is called linear progression.

End-Stage DifferentiationAs these cells continue to go

along this pathway they are able todivide and expand their numbers.

They then undergo a terminal dif-ferentiation into their final form.This end-stage differentiation pro-duces a cell that has a specific half-life that will eventually expire.7

This end-stage differentiation oc-curs when cell division stops. Thereare no unique markers known formesenchymal stem cells, but theircell surface antigen profile has beeninvestigated, and a comprehensivelist of surface markers have been doc-umented. Mesenchymal stem cells,by definition, must be positive forthe following surface markers SH2,SH3, CD29, CD44, CD71, CD73,CD90, CD105, CD106, CD120,CD124, and CD166 while negativefor CD45, CD 34, and CD14.

Hematopoietic Stem CellsHematopoietic stem cells are

positive and exclusive for CD 34and CD 45. Other identifying char-acteristics of osteogenic mesenchy-

mal stem cells include biochemicalindicators such as alkaline phos-phatase, osteocalcin, and the pro-duction of a calcium rich mineral-ized extracellular matrix.8

Studies have shown that inject-ed mesenchymal stem cells havehastened hematopoietic recoveryafter bone marrow transplantation,and their immune-regulatory prop-erties facilitate engraftment oftransplanted organs and reducegraft-versus host disease.9 This ef-fect was initially described for Tcells. In vitro studies demonstratedthat mesenchymal stem cells wereable to suppress T lymphocyte acti-vation and proliferation in re-sponse to alloantigens and non-specific mitogens.10

Allogenic MesenchymalStem Cells

Allogenic mesenchymal stemcells do not express class II anti-gens, and therefore do not provokean adverse host response. Class IIsurface antigens are required for ahost to mount a T-Cell reaction toforeign cells. Two important prod-ucts that stem cells produce arebone morphogenetic proteinswhich are needed for osteo-induc-tion and cytokines that modulatean anti-inflammatory and immuneresponse.

Bone marrow has two types ofstem cells, those that are ofhematopoietic origin, and ones de-rived from the mesoderm. Mes-enchymal stem cells are small innumber compared to hematopoiet-ic ones. They only represent about.01% of nucleated bone cells.11 Thehighest concentrations of mes-enchymal stem cells are found inthe pelvic girdle and the vertebralbodies. When the iliac crest is aspi-rated, there are roughly betweenone to five mesenchymal stem cellsper 500,000 nucleated cells.

On average, in 1 cc. of adultmarrow from an iliac crest, therewill be a yield of roughly 1,000 to1,500 mesenchymal stem cells.12

Caplan has documented that thenewborn has one mesenchymalstem cell per 10,000 marrow cells.Teenagers have one mesenchymalstem cell per 100,000 marrow cells.At age thirty, there is one per250,000 marrow cells, and at age


212 www.podiatrym.comPODIATRY MANAGEMENT • JUNE/JULY 2010

Stem Cells...

der Maxinow used histologicalfindings to describe a single pre-

cursor cell within the mesenchymalcell that differentiates into varioustypes of blood cells.1

Anatomy and EmbryologyWhen the embryo forms, the

mesoderm, which is the middle celllayer, eventually differentiates intobone, cartilage, fat, dermis, or otherconnective tissue.2 This develop-mental process is relatively rapid.The original embryological genesisof discrete morphologies requires aunique series of signaling eventsthat most likely function duringthe embryonic process which iscalled the mesengenic process. Thisprocess occurs in steps in whichthere are cellular transitions frommesenchymal stem cells to highlydifferentiated phenotypes. Thisprocess continues throughout mat-uration and adulthood but at a sig-nificantly slower pace than in theembryo, but continues throughoutlife to ensure that once tissue getsinjured, it is repaired. There areother signals that control the main-tenance and repair involved in re-generating existing structures.3

The mesenchymal stem cells ata repair site mitotically expand andform a repair blastema that spansthe break of tissue discontinuity;this blastema eventually differenti-ates into the appropriate skeletaltissues as determined by the localconcentration of surrounding tis-sue-specific cytokines and growthfactors.4 The reason why there islimited tissue repair in the adultcompared to the embryo is thatthere are too few mesenchymalstem cells in the adult.5

Repair of Injured TissueThe process of repair of injured

tissue or bone is very similar. Mes-enchymal stem cells are situatedthroughout the body as pericytes.With the disruption of blood ves-sels in or near the injured tissue,stem cells are liberated from thepericytes; these cells divide and se-crete bio-active factors that func-tion to protect and repair or regen-erate the injured tissue. The secre-tory products of mesenchymal stemcells at sites of injury strongly re-

Continuing

MedicalEducation

For a mesenchymal

stem cell to turn

into bone, a bone

morphogenetic

protein signals this

differentiation.


available patients responded tomesenchymal stem cells with a re-duction in acute (partial and com-plete) response. 77% of the patientshad a complete response of graftversus host disease (complete reso-

lution of disease)by day 28, indi-cating a durableresponse to treat-ment.

At sixmonths, 61% ofthe patients treat-ed with mes-enchymal stemcells still had adurable responserequiring no addi-tional immuno-suppressive thera-py, clinical inter-vention, or in-creased steroid

use.15 Previously published data in-dicates that less than 35% of pa-tients achieve this endpoint whentreated with steroids alone.

In an open-label phase-2 trialtesting for treat-ment - re s i s t antCrohn’s disease,every patienttreated had a re-duction in diseaseseverity by day28. In patientswho failed avail-able drugs forCrohn’s disease,there was a statis-tically significantreduction in themean Crohn’sDisease ActivityIndex (CDAI)score of 105points by day 28.

The improve-ment was rapidwith an averageCDAI reductionof 62 points byday 7. There ap-peared to be apositive correlation between doseand response, with patients receiv-ing the high dose achieving agreater response (average CDAI re-duction of 137 vs. 65). In this dif-ficult-to-treat population that hadfailed previous therapies, one-third of the patients achieved clin-

eighty, there is one mesenchymalstem cell per 2 million marrowcells.13

Along with age, mesenchymalstem cells are de-creased with alco-hol abuse, sys-temic illness, andosteoporosis.

Properties ofMesenchymalStem Cells

As describedabove, mesenchy-mal stem cellshave the abilityto be transplant-ed between un-matched donorand recipientwithout stimulat-ing an immune response. Whendealing with the human skeleton,mesenchymal stem cells are neededfor the remodeling and repair ofbone and other tissue. The seminalevent for all bone formation is themesenchymal stem cell’s differenti-ation into an osteoblast.

Once the bone morphogeneticproteins activate the mesenchymalstem cells, osteoblasts are formed tolay down new bone. These os-teoblasts will either die or becomeosteocytes. Mesenchymal stem cellshave the ability to seek out dam-aged tissue whether it is with a frac-ture, myocardial infarction, or is-chemic brain injury.14

Clinical ApplicationsCurrently, there is a significant

amount of research regarding theuse of adult mesenchymal stemcells. This research is related toboth allografts and autografts. Dueto the fact that mesenchymal stemcells possess anti-inflammatory andimmune properties, there are cur-rent studies using the cells for graftversus host disease, along withCrohn’s disease.

The low immunogenicity ofthese cells suggests that mesenchy-mal stem cells can be transplanteduniversally without matching be-tween donors and recipients. In anopen-label trial studying treatmentof newly diagnosed graft versushost disease, 94% (29 out of 31) of

Stem Cells... ical remission of theirdisease.16

CardiomyocytesMesenchymal stem cells can

also be induced to differentiate invitro into cardiomyocytes, whichhas stimulated a large number ofanimal and clinical studies to eval-uate the efficacy of mesenchymalstem cells for cardiac repair and re-generation.17

In a recent issue of the Journalof the American College of Cardiol-ogy, a group of 53 patients whohad myocardial infarction werestudied for two years. These pa-tients were implanted with allograftadult mesenchymal stem cells with-in ten days of the event. The studywas a double-blinded and random-ized control. The study participantshad an MRI and an echocardiogramat six months.

Patients who had received thestem cells had evidence of newblood vessel formation and a de-crease in arrhythmias. The hypoth-esis is that adult mesenchymal stem

cells have the po-tential to developinto mature heartcells and formnew blood ves-sels.18 Difficultiesmay arise, howev-er, because of thebroad differentia-tion capacity ofm e s e n c h ym a lstem cells. Thereremains signifi-cant heterogene-ity among mes-enchymal stemcell populationsand thus they areless predictablewhen implanted.Most notably,some studiesfound that im-planted mes-enchymal stemcells had differen-

tiated into osteoblasts inside ven-tricular tissue.19

OsteoarthritisAnother example in which

adult mesenchymal stem cells arebeing investigated is its use in os-


Continuing

Medical Education

A study that

compared human

mesenchymal stem

cells derived from bone

marrow, periosteum,

synovium, skeletal

muscle, and adipose

tissue revealed that

synovium-derived

mesenchymal stem

cells exhibited the

highest capacity for

chondrogenesis.

In an open-label

phase-2 trial testing

for treatment-resistant

Crohn’s disease,

every patient treated

had a reduction

in disease severity

by day 28.

to attach and mi-grate. There are bothsynthetic and naturalscaffolds. Syntheticscaffolds can be de-signed to have all theabove characteristics.They are usuallymade of alpha hy-droxyl polyester.24

Native scaffolds,including collagentype I, hyaluronan,chitosan and alginatepresent a more natu-ral micro-environ-ment for the mes-enchymal stem cellsthan synthetic scaf-folds do.25

Collagen Type IHydrogels

Collagen type Ihydrogels have several advantages.These matrices are biodegradable,can be metabolized by mesenchy-mal stem cells via the action of en-

dogenous collage-nases, elicit mini-mal, if any, in-flammation, andsurround the mes-enchymal stemcells in three di-mensions. Thematerial proper-ties of collagenhydrogels are sim-ilar to those ofhyaline cartilage.Collagen gels canalso be adapted as

desired to most defect shapes.26

Compared with meshes or fleeces,in which cellseeding is oftenlimited to su-perficial regionsof the scaffoldmaterial, hy-drogels permita more evendistribution ofseeded mes-enchymal stemcells, whichpromotes ho-m o g e n e o u sproduction ofextracellularmatrix.27

The first

results for use oftransplanted mes-enchymal stem cellsseeded within colla-gen type I hydrogelsto repair isolated,full-thickness, carti-lage defects in hu-mans was reportedby Wakitani, et al.Two patients with apatellar defect weretreated with collagengels containing mes-enchymal stem cells,which were coveredwith a periostealflap. Fibrocartilagi-nous filling of thedefects was foundafter one year, andboth patientsshowed significantlyimproved clinical

outcomes in their respective follow-ups after one, four, and five years.28

Rheumatoid ArthritisAnother area of research is treat-

ing rheumatoid arthritis, both thephysical and immune aspect of thedisease. Although it is still debat-able, rheumatoid arthritis is be-lieved to be a T cell-driven inflam-matory synovitis disease in which Tcells and synoviocytes participatein a complex network of cell- andmediator-driven events leading tojoint destruction.

Joint destruction in rheumatoidarthritis and the anti-inflammatoryand immune-suppressive propertiesof mesenchymal stem cells suggestthat rheumatoid arthritis may be a



Stem Cells...

teoarthritis. One of the formsof tissue that mesenchymal stem

cells can differentiate into is carti-lage. The cells can be stimulatedinto chondrogenesis, and can beexpanded in the laboratory.

A study that compared humanmesenchymal stem cells derivedfrom bone marrow, periosteaum,synovium, skeletal muscle, and adi-pose tissue revealed that synovium-derived mesenchymal stem cells ex-hibited the highest capacity forchondrogenesis, followed by bonemarrow derived and periosteum-de-rived mesenchymal stem cells.20

Certain growth factors such asfibroblasts and transforminggrowth factor beta are used in an invitro environment to grow newcells.21 Optimization of chondroge-nesis to generate stable cartilagesuitable for clinical use is likely cellsource-dependent, and will likelybe a function of cellular context,microenvironment, as well as prop-erties of dose andtiming of themolecules admin-istered to thecells.22

Mesenchymalstem cells havebeen transplantedin various waysinto joints. Inone study, autol-ogous mesenchy-mal stem cells ina dilute solutionof sodiumhyaluronan were directly injectedinto the knee joints of goats, inwhich osteoarthritis had been in-duced by a total medial meniscec-tomy and resection of the anteriorcruciate ligament. The joints thatwere exposed to mesenchymal stemcells showed evidence of marked re-generation of the medial meniscus,and implanted cells were detectedin the newly formed tissue.23

Another method of applicationin a joint is via a scaffold. The idealtemplate should have the followingcharacteristics: it needs to be bio-degradable and bio-compatiblealong with being porous to allowthe cells to penetrate and to havetissue in-growth. It should alsohave a surface that allows the cells

Continuing

MedicalEducation

Trinity Evolution

has an addition

of a cancellous

bone matrix that

functions as a

scaffold.

Figure 2: Application of stem cells in non-union site.

Figure 1: X-ray showing delayedunion at 5 months.


ed by Orthofix and the MTF foun-dation. These cells have under-gone a selective depletion of im-munogenic cells. The product alsohas an addition of a cancellousbone matrix that functions as ascaffold. The graft has all three

properties of an autograft. It is os-teoinductive, osteoconductive, andosteogenic.

The production of Trinity Evo-lution begins within 96 hourspost-mortem and is completedwithin 24 hours. Donors arescreened and tested for over 50

diseases and illnesses. The tissue isfrozen within one hour after pro-cessing. The health of the cell isbest controlled by freezing slowand thawing fast. Rapid freezingcan obviously damage the cells.The cells are stored at -80 degrees.

candidate disease for cartilage andbone repair using mesenchymalstem cells therapy.

Mesenchymal stem cells canalso inhibit the proliferation ofautologous and allogeneic periph-eral blood mononuclear cells in adose-dependent manner. The in-hibition was observed with mes-enchymal stem cells and peripher-al blood mononuclear cells, eitherfrom healthy donors or from pa-tients suffering from autoimmunediseases.29

Bone HealingThe gold standard of bone grafts

is the cancellous autograft, which istraditionally harvested from the pa-tient’s iliac crest. The iliac crest isthe ideal donor site because it con-tains mesenchymal stem cellswhich are osteogenic, osteoinduc-tive and osteoconductive. Eventhough an autograft is the goldstandard, there are some challengesthat can occur with using an iliaccrest graft. These issues include alimited supply of donor material,donor site morbidi-ty/pain, and the vari-able amounts or incon-sistent amounts ofmesenchymal stemcells.30

Most allografts donot have all threeproperties of auto-grafts. For instance,demineralized bonematrix is osteo-induc-tive and stimulates thefusion of bone due tothe bone morpho-genetic proteins thatinduce or stimulate themesenchymal stemcells. Synthetics mate-rials such as ceramichydroxyapatite are os-teoconductive and fa-cilitate bony ingrowthonly.

Trinity EvolutionCurrently, there are only two

commercially-available mesenchy-mal stem cell products availableon the market. Osteocel by Nuva-sive is marketed to spinal sur-geons. Trinity Evolution is market-

Stem Cells... Every lot is tested for vi-ability and osteogenicity.Each lot of Trinity Evolutionhas a minimum of 250,000 cellsper cc. There is greater than 70%cell viability along with in-vitroosteogenic capacity.

Before implantation, TrinityEvolution is thawed in a warmsaline bath between 35-39 Celsiusfor roughly 30 minutes. The jarshould remain in solution untilcontents flow freely upon inver-sion. The cryoprotectant is decant-ed, and D5 lactated ringers is addeduntil used. The D5LR is decantedoff before being implanted.

Rush, et al. published a retro-spective analysis of revisional footand ankle surgery in the Journal ofFoot and Ankle Surgery.31 In thisstudy, 23 patients were reviewedwho had implantation of mes-enchymal stem cells after revisionalfoot or ankle surgery. A radiograph-ic review was performed and therewas radiographic new bone forma-tion at the areas of implantationand a 91.3% union rate was ob-served. Statistical tests were per-formed to determine whether gen-

der, diabetes, chronicrenal insufficiency, orsmoking were associatedwith time to healing.These statistical tests didnot show any influencein time to heal.

Case PresentationA sixty year old fe-

male presented to theclinic with a chief com-plaint that she fell off afour foot step ladder.She stated that she wentto the local emergencyroom where x-rays weretaken. The x-rays re-vealed a comminutedmid-shaft 5th metatarsalfracture of the left foot.Due to the severity ofthe fracture, open reduc-tion internal fixationwas determined to be

the procedure of choice.A complete history and physical

was performed. Significant findingswere thrombocytopenia, Raynaud’sdisease, coronary artery disease,and a 50 year pack-a-day year histo-


Continuing

Medical Education

Adult

mesenchymal

stem cells offer

promising results

for many medical

and surgical

conditions.

Figure 3: Post-operativex-ray.

Figure 4: 12 week post-operativex-ray showing complete union.

plan AI. Age Related influences on the os-teogenic potential of marrow derivedmesenchymal cells. Bone. 13:69-80, 1992.

6 da Silva Meirelles, et al. In search ofthe In Vivo Identity of the MesenchymalStem Cells. Stem Cells. 9: 2287-3399,2008, Vol. 26.

7 Caplan AI, Fiszman MY. Molecularand Cell Isoforms During Development.Science. 221:921-927, 1983.

8 Dominici M, Le Blanc K, et al. Min-imal criteria for defining multi potentmesenchymal stromal cells. Cytotherapy.8:315-317, 2006.

9 Le Blanc K, Rasmusson I, Sundberg,et al. Treatment of of severe acute graftversus host disease with third party hap-loidentical mesenchymal stem cells.Lancet. 363:1439-1441, 2004.

10 Di Nicola M, Carlo-Stella C, et al.Human bone marrow stromal cells sup-press T-lymphocyte proliferation inducedby cellular or nonspecific mitogenic stim-uli. Blood. 99: 3838-3843, 2002.

11 Pittenger, MF, et. al. Multilineagepotential of adult human mesenchymalstem cells. Science. 284:143-147, 199.

12 Risbud MV, et. al. Osteogenic po-tential of adult stem cells of the lumbarvertebral body and the illiac crest. Spine.31: 81-89, 2006, Vol. 1.

13 AI, Caplan. The Mesegenic Process.Clinics in Plastic Surgery. 3; 429-435,1994, Vol. 21.

14 Shake JG, et al. Mesenchymal stemcell implantarion in a swine myocardialinfarct model. Engraftment and function-al effects. Ann. Thorac. Surg. 73: 1919-1925, 2002.

15 Kebriaei P, Adult human mes-enchymal stem cells added to corticosteri-od therapy for the treatment of acutegraft-versus host disease. Biol Blood Mar-row Transplant. 15:804-811, 2009, Vol. 7.

16 Dryden, GW. Overview of stemcell therapy for Crohn’s disease. ExpertOpin Biol Ther. 7;841-847, 2009, Vol. 9.

17 Makino, S., et al. Cardiomyocytescan be generated from marrow stromalcells in vitro. Journal of Clinical Investi-gation. 103;697-705, 1999.

18 Hare JM, et. al. A Randomized,Double-Blind, Placebo-Controlled, Dose-Escalation Study of Intravenous AdultHuman Mesenchymal Stem Cells(Prochymal) After Acute Myocardial In-farction. J Am Coll Cardiol. 54; 2277-2286, 2009.

19 Yoon, Y.S. et al. Unexpected severecalcification after transplantation of bonemarrow cells in acute myocardial infarc-tion. Circulation. 109; 3154-3157, 2004.

20 Sakaguchi Y, et al. Comparison ofhuman stem cells derived from variousmesenchymal tissues:superiority of syn-ovium as a cell source. Arthritis Rheum.52:2521-2529, 2005.

21 Im GI, et al. Chondrogenic differ-entiation of mesenchymal stem cells iso-

lated from patients in late adulthood: theoptimal conditions of growth factors. Tis-sue Eng. 12;527-536.

22 Chen FH, Rousche KT, Tuan RS.Technology insight: adult stem cells incartilage regeneration and tissue engi-neering. Nat Clin Pract Rheumatol.2:373-382, 2006.

23 Murphy JM et al. Stem cell therapyin a caprine model of osteoarthritis.Arthritis Rheum. 48: 3464-3474, 2003.

24 Li WJ, et al. Application of nanofi-brous scaffolds in skeletal tissue engineer-ing. J Biomed Nanotechnol. 1: 1-17,2005.

25 Kuo CK, et al. Cartilage tissue engi-neering: its potential and uses. Curr OpinRheumatol. 18: 64-73, 2006.

26 Nöth U, et al. Chondrogenic differ-entiation of human mesenchymal stemcells in collagen type I hydrogels. JBiomed Mater Res. A 83: 626-635, 2007.

27 Nöth U, et al. Chondrogenic differ-entiation of human mesenchymal stemcells in collagen type I hydrogels. JBiomed Mater Res. A 83: 626-635, 2007.

28 Wakitani S, et al. Autologous bonemarrow stromal cell transplantation forrepair of full-thickness articular cartilagedefects in human patellae: two case re-ports. Cell Transplant. 13: 595-600, 2004.

29 Bocelli-Tyndall C, et al. Bone mar-row mesenchymal stromal cells (BM-MSCs) from healthy donors and stromalcells (BM-MSCs) from healthy donors an-dautologous- and allogeneic-stimulatedlymphocytes in vitro. Rheumatology (Ox-ford). 46:403-408, 2007.

30 Laurie SWS, et al. Donor-site mor-bidity after harvesting rib and illiac bone.Plast Reconstr Surg. 73:933-938, 1984.

31 Rush S, Hamilton G, Ackerson L.Mesenchymal Stem Cell Allograft in Revi-sion Foot and Ankle Surgery: A Clinical andRadiographic Analysis. Journal of Foot andAnkle Surgery. 10: 163-169, 2009, Vol. 48.


Stem Cells...

ry of smoking. Medicationsincluded aspirin, atenolol,

bupropion, etodolac, felodipine,furosemide, lorazepam, omepra-zole, and pravastatin. Her lower ex-tremity exam was unremarkable,except for ecchymosis and edemapresent at the fracture site on theleft foot.

Surgery was performed whichincluded ORIF, utilizing plate fixa-tion. The patient was put in anon-weight bearing cast for sixweeks. Serial x-rays were taken ona bi-weekly basis. A pulsed electro-magnetic field bone stimulatorwas dispensed at eight weeks post-op due to slow consolidation ofthe fracture site. At five monthspost-op, it was determined thatthere was a delayed union whichwould most likely go on to a non-union (Figure 1).

The delayed non-union wasmost likely due to the patient’scontinued use of nicotine. The pa-tient was brought back to surgerywhere the plate was removed, andTrinity mesenchymal (Figure 2)stem cells were put in the non-union site after the fibrous tissuewithin the site was removed. An ex-ternal fixation device was appliedand the patient was put in a non-weight bearing cast (Figure 3). Seri-al x-rays were taken and completeunion was seen at approximately12 weeks (Figure 4).

ConclusionAdult mesenchymal stem cells

offer promising results for manymedical and surgical conditions.Even though recent research hasshown promising results for footand ankle surgery, further researchstill needs to be done. �

References1 Stewart, Sell. Stem Cell Handbook.

s.l.: Humana Press, 2003, p. 143.2 Balinsky, BI. An Introduction to

Embryology. Philadelphia : WB Saunders,1975. 4.

3 Joyce ME, Roberts AB. Transform-ing growth factor beta and the intiationof chondrogeneis and osteogenesis in therat femur. J Cell Biol. 1990, Vols. 110;2195-2207.

4 Caplan AI, Bone Development andRepair. Bioessays. 6:171-175, 1987.

5 Haynesworth SE, Young RG, Ca-

Continuing

MedicalEducation

Dr. HowardKimmel holds aBA in Chemistryfrom the Uni-versity of SouthFlorida, a Doctorof PodiatricMedicine degreefrom the OhioCollege of Podi-atric Medicine,and an MBA in Healthcare from Cleve-land State University. Dr. Kimmel isboard certified by the American Boardof Podiatric Surgery. He is the residen-cy director for podiatric surgery at theLouis Stokes Department of VeteransAffairs and is a clinical senior instruc-tor in the Department of Surgery atCase Western Reserve UniversitySchool of Medicine in Cleveland, Ohio.


7) 1 cc. of bone marrow aspiratefrom the iliac crest yields approx-imately:A) 10 mesenchymal stem cellsB) 100 mesenchymal stemcellsC) 1,000 mesenchymal stemcellsD) 10,000 mesenchymal stemcells

8) As we age, the amount ofmesenchymal stem cells:A) Stay the sameB) DecreaseC) IncreaseD) Turn into hemopoeticstem cells

9) When mesenchymal stem cellsturn into osteoblasts, they arestimulated by:A) OsteoclastsB) Transforming growth fac-tor betaC) CalciumD) Bone morphogenetic pro-teins

10) Mesenchymal stem cells arestored throughout the body as:A) OsteocytesB) ChondrocytesC) PericytesD) Leukocytes

11) In which one of the follow-ing conditions are mesenchymalstem cells not used?A) Chronic lymphocyticleukemiaB) Crohn’s diseaseC) Rheumatoid arthritisD) graft vs. host

1) Which one of the followingmarkers is not found on an adultmesenchymal stem cell?A) Cd29B) Cd44C) Cd45D) Cd 120

2) Class II surface antigens arerequired to launch a reaction for:A) AntihistaminesB) IGeC) T-cellsD) Macrophages

3) Adult mesenchymal stem cellsare:A) MultipotentB) UnipotentC) TotipotentD) Tripotent

4) An adult mesenchymal stemcell can NOT differentiate intoa/an:A) AdiposeB) CartilageC) NeutrophilD) Bone

5) Adult mesenchymal stem cellsare derived from the:A) EndodermB) MesodermC) EctodermD) Tetraderm

6) When an adult mesenchymalstem cell expands via mitosis itforms a/an:A) BlastemaB) NeutrophilC) OsteoclastD) Fibrin

12) In Crohn’s disease, whatpercentage reduction ofsymptoms did patients getafter receiving mesenchymalstem cells?A) 20%B) 40%C) 80%D) 100%

13) When patients withmyocardial infarction weretreated with mesenchymalstem cells, there was a de-crease in arrhythmias andalso:A) increase in new bloodvessel formationB) increase in infarctionsC) decrease in alkalinephosphataseD) pulmonary edema

14) There has been publishedevidence that difficulty canarise when implantingmesenchymal stem cells inthe heart because they candifferentiate into:A) CardiomyocytesB) LeukocytesC) OsteoblastsD) Keratinocytes

15) The mesenchymal stemcell that has the highestpotential for chondrogenesisis derived from:A) synoviumB) boneC) muscleD) adipose

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E X A M I N A T I O N

See answer sheet on page 219.


218 PODIATRY MANAGEMENT

16) Which one of the following is notconsidered a native scaffold for deliveringstem cells?A) CollagenB) AlginateC) Alpha hydroxyl polyesterD) Hyaluaron

17) The ideal scaffold for delivering adult mes-enchymal stem cells for regeneration of carti-lage should be:A) PorousB) BiodegradeableC) BiocompatibleD) All the above

18) The ideal donor bone should have thefollowing characteristics:A) osteoinductiveB) osteoconductiveC) osteogenicD) all of the above

19) Commercially-available mesenchymal stemcells that are used for bone have ____________added to them?A) cortical boneB) cancellous boneC) bone morphogenetic proteinD) hydroxyappetite

20) Commercially-available bone mesenchymalstem cells have:A) 25 stem cells per ccB) 250 stem cells per ccC) 25,000 stem cells per ccD) 250,000 stem cells per cc

E X A M I N A T I O N

(cont’d)

See answer sheet on page 219.

Continuing

MedicalEducation

PM’sCPME Program

Welcome to the innovative Continuing EducationProgram brought to you by Podiatry ManagementMagazine. Our journal has been approved as asponsor of Continuing Medical Education by theCouncil on Podiatric Medical Education.

Now it’s even easier and more convenientto enroll in PM’s CE program!

You can now enroll at any time during the yearand submit eligible exams at any time during yourenrollment period.

PM enrollees are entitled to submit ten examspublished during their consecutive, twelve–monthenrollment period. Your enrollment period beginswith the month payment is received. For example,if your payment is received on September 1, 2006,your enrollment is valid through August 31, 2007.

If you’re not enrolled, you may also submit anyexam(s) published in PM magazine within the pasttwelve months. CME articles and examinationquestions from past issues of Podiatry Man-agement can be found on the Internet athttp://www.podiatrym.com/cme. Each lessonis approved for 1.5 hours continuing education con-tact hours. Please read the testing, grading and pay-ment instructions to decide which method of partici-pation is best for you.

Please call (631) 563-1604 if you have any ques-tions. A personal operator will be happy to assist you.

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The Podiatry Management Magazine CMEprogram is approved by the Council on PodiatricEducation in all states where credits in instruction-al media are accepted. This article is approved for1.5 Continuing Education Contact Hours (or 0.15CEU’s) for each examination successfully completed.

www.podiatrym.com

Home Study CME credits nowaccepted in Pennsylvania

Over, please

Please print clearly...Certificate will be issued from information below.

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higher on any examination will receive an official computer formstating the number of CE credits earned. This form should be safe-guarded andmay be used as documentation of credits earned.

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(3) All answers should be recorded on the answer formbelow. For each question, decide which choice is the best an-swer, and circle the letter representing your choice.

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ENROL LMENT FORM & ANSWER SH E E T

�

219

Continuing

Medical Education

exam during your current enrollment period. If you are not en-rolled, please send $20.00 per exam, or $139 to cover all 10 exams(thus saving $61* over the cost of 10 individual exam fees).

Facsimile GradingTo receive your CPME certificate, complete all information and

fax 24 hours a day to 1-631-563-1907. Your CPME certificate willbe dated and mailed within 48 hours. This service is available for$2.50 per exam if you are currently enrolled in the annual 10-examCPME program (and this exam falls within your enrollment period),and can be charged to your Visa, MasterCard, or American Express.

If you are not enrolled in the annual 10-exam CPME pro-gram, the fee is $20 per exam.

Phone-In GradingYou may also complete your exam by using the toll-free ser-

vice. Call 1-800-232-4422 from 10 a.m. to 5 p.m. EST, Mondaythrough Friday. Your CPME certificate will be dated the same dayyou call and mailed within 48 hours. There is a $2.50 charge forthis service if you are currently enrolled in the annual 10-examCPME program (and this exam falls within your enrollment peri-od), and this fee can be charged to your Visa, Mastercard, Ameri-can Express, or Discover. If you are not currently enrolled, the feeis $20 per exam. When you call, please have ready:

1. Program number (Month and Year)2. The answers to the test3. Your social security number4. Credit card information

In the event you require additional CPME information,please contact PMS, Inc., at 1-631-563-1604.

Enrollment/Testing Informationand Answer Sheet

�


ENROL LMENT FORM & ANSWER SH E E T (cont’d)Continuing

MedicalEducation

LESSON EVALUATION

Please indicate the date you completed this exam

_____________________________

How much time did it take you to complete the lesson?

______ hours ______minutes

How well did this lesson achieve its educationalobjectives?

_______Very well _________Well

________Somewhat __________Not at all

What overall grade would you assign this lesson?

A B C D

Degree____________________________

Additional comments and suggestions for future exams:

__________________________________________________

__________________________________________________

__________________________________________________

__________________________________________________

__________________________________________________

__________________________________________________

1. A B C D

2. A B C D

3. A B C D

4. A B C D

5. A B C D

6. A B C D

7. A B C D

8. A B C D

9. A B C D

10. A B C D

11. A B C D

12. A B C D

13. A B C D

14. A B C D

15. A B C D

16. A B C D

17. A B C D

18. A B C D

19. A B C D

20. A B C D

Circle:

EXAM #5/10The Use of Adult Mesenchymal Stem Cells

in Reconstructive Foot Surgery(Kimmel)

theuse objectives ofadult mesenchymal stemcells ... cme.pdf · stemcells asdescribed above,mesenchy...

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