Dr. Pradeep Mahajan Profile

A Journey From Pills to Cells | Dr Pradeep Mahajan | 1

GIST OF PROFILE

CHAIMAN & MANAGING DIRECTOR STEMRX BIOSCIENCE SOLUTIONS PVT. LTD.• Guiding a well qualified team of scientists and

researchers working 24x7 for developing cellularmedicineprotocolsforvariousdisorders.

• Looking forward to taking this therapy to thecommonman

DIRECTOR DR. P. V. MAHAJAN HOSPITAL & INDUSTRIAL TRAUMA CARE CENTRE• Providing services for trauma care / industrial

injuries• OccupationalHealthHazardmanagementservices.

DIRECTOR SIDDHARTH MARINE HEALTH SERVICES PVT. LTD.• Consultationandemergencymanagement

DIRECTOR MEDI-CHECK HEALTH SERVICES PVT. LTD.• Corporatehealthcheck-upsataffordablerates• Occupationalhealthservices

HON. UROSURGEON AND CONSULTING SURGEON • Continues to perform surgical procedures as

honorary charitable service at MATHADI TRUSTHOSPITAL

• Associate Professor for department of Surgery atCooperHospitalofMCGM,Mumbai

VISION & MISSION• To make all incurable disorders / non-treatable

diseasestreatableandimprovethequalityoflifeofeverylivingbeing.

PHILOSOPHY OF PROFESSION“Be focused and work towards excelling in your goal. Compete with yourself and not others.”

“Never say no to a patient.’’

MOST PROUD OF• Mydecisiontochangefrombeingageneralsurgeon

and academician to a regenerative medicineresearcher has proved to be a game changerwhichenabledmetoexplore theunexplored inapassionateandsuccessfulmanner.

CHARACTER STRENGTHS• Commitmentanddedication• Perseverance• Convincingcommunication• Simplicity

LANGUAGE FLUENCY• English• Hindi• Marathi

HIGHER EDUCATION• M.S.• AFIH• Diploma in Urology from University of Vienna,

Austria

A DAY IN MY LIFE

Patientsforcounsellingandprocedures

Self-development

Dr. PRADEEP V. MAHAJANUROSURGEON AND REGENERATIVE MEDICINE RESEARCHER

@ [email protected] www.stemrx.in Andheri,Mumbai,India

Colleaguesand

supportingstaffforsmoothworkingandtheir

professionaldevelopment

Family

2 | Dr Pradeep Mahajan | A Journey From Pills to Cells

INDEXCITATION 04

PROFILE GeneralProfile Academics 06 Academicachievements 06 Teachingexperience 06 Trainingprogrammes 07 Researchexperience Researchpapersandarticlespublished 07 Articles/abstracts 07 Currentengagements 08 Awards And Accolades Awards 09 Landmark Achievements 10 SocialActivities 10 Associate Memberships 11 Patents 11 Keynote Address Internationalconferences 11 Nationalconferences 11

MEDIA COVERAGE Print Media 12 Articlesinnewspaper Electronic Media ‘Hitguj’-Zee24Taas 12 Miscellaneous 14

SUCCESS STORIES THOSE CREATED HISTORY 64

CASE STUDY Neurogenicbladder 68

CERTIFICATES TheOhioStateUniversity 71 9thannualtranslationaltoclinicalregenerativemedicine 71woundcareconference Indianstemcellstudygroupmeeting 72 Ioracon-2015 72 Participationasdelegate/facultyin‘Anupdateinvariousmedical 73 managements’


ParticipationinCMEbyIndianMedicalAssociation,NaviMumbai 73 Participationasdelegatein‘Practicemanagementofdoctors’. 74 ‘MASCON-2012:BasicsandBeyond’ 74 ParticipationinCMEbyIndianMedicalAssociation,NaviMumbai 75 ParticipationinCMEbyIndianMedicalAssociation,NaviMumbai 76 ParticipationasafacultyinCMEbyIndianMedicalAssociation, NaviMumbai 76 AMCON2011-12 77 SriRaghavendrabiotechnologiespvt.ltd. 77 RotaryClubofBombay,Airoli 77 Antiagingcomprehensivecertification 78 Certificateofregistration(DirectorateGeneralFactoryAdvice ServiceandLabourInstitutes) 78 Indianachiever’sawardforhealthexcellence 79 Participationinbasiclaparoscopicsurgerytrainingprogramme 80 EMCON-2004 80 UrologicalsocietyofIndia 81 Specialexecutivemagistrates’society 81 Fellowshipinurology,Vienna 82 Americanmedicalsociety,Vienna 82 Internshipcompletioncertificate(MarathwadaUniversity) 83 MBBS(MarathwadaUniversity) 83 MaharashtraMedicalCouncil 83 Registrationcertificateforadditionalmedicalqualification 84 2016leadersawards 84 Nationalawardforexcellenceinhealthcare 84

PUBLICATIONS 85


Citation

Dr.PradeepMahajanisaleadingstem cell researcherandstem cell transplant surgeonratedasoneofthebestamongthetopfew renowned clinical stem cell researchers. He has received‘2016 Leadership award’ forhis company ‘StemRxBioscienceSolutionsPvt.Ltd.’forthefastestgrowinghealthcarebrandforstemcelltreatmentinMaharashtraandalso‘NationalAwardsfor Excellence in Healthcare’ for the Best Clinical ResearchCompanyin2016.A pioneerinthefieldofstemcellresearch,hehasbeenamongstthefirstfewtorecognizeenormous potential of stem cellsandtotreatthepatientswaitingforcurewiththis

amazing technology.HehasreceivedaGold Medal from Special Executive Magistrates’ SocietyofMumbaiforservices in trauma care on highway.Hehasalsoreceived‘IndianAchieverAwardforHealthcareExcellence’in2006.

Dr.P.V.Mahajanisagraduate of SRTR Medical CollegefromMarathwadaUniversitywithlaurelsoftwo gold medals in MS(MasterinSurgery)fromMarathwadaUniversity.Hehasalsoreceived‘Late Shri Narayanrao Chitgopekar Prize’ for the best performance in MS (General Surgery)examinationheldinNovember1987atMarathwadaUniversity.HeholdsDiploma in UrologyfromVienna Universityandisamember of American Medical Society of Vienna.Hehasundergoneseveraltrainingcoursesinstemcellsandregenerativemedicineandisknownforhisprofoundknowledge in cellularmedicine. Amongst the various training programmes, training at Ohio State University, USisnoteworthy.HehasalsoobtainedanAssociate Fellowship of Industrial HealthfromtheCentral Government’s Labour Institute,Laparoscopic Surgical trainingandacertificate course from KEM Hospital.

Dr.PradeepMahajanhasgotnumerousnationalandinternationalrecognitionsforhisresearchand innovativework in thefieldof clinical research in regenerative medicine andcell based therapy.ThisgothimthemostdignifiedappointmentofhonouraryprofessorforregenerativemedicineandcellbasedtherapiesinCooperHospital,Mumbai.HewasalsohonouredbytheGovernmentofIndiaandGovernmentofMaharashtrabyappointingasconsultant and panel doctor with the director general of shipping and labour department.Dr.Mahajanisamemberof board of studies in ITMUniversity, Raipur for PhD courses in stem cells and regenerativemedicine. For his outstanding contribution in the field of clinical research in regenerativemedicineandcellbasedtherapy,Dr.Mahajanhasbeenfelicitatedby‘TheCentreofRegenerativemedicineandCellBasedTherapies’,OhioStateUniversity,US,in2015whichalsoinvitedhimtoparticipateintheexclusivetrainingprogrammeinorgandevelopmentandtissueengineering.HehasworkedasanassociateprofessorofsurgeryatTernaMedicalCollege,NaviMumbai.

Dr.PradeepMahajanisFounder and Chairman as well as Managing Director of StemRx Bioscience Solutions Pvt. Ltd. Under his dynamic and able guidance, several scientists and researchersareworking 24x7, developing cellularmedicine protocols in various treatmentmodalities ofdiseases and disorders of orthopaedic conditions, metabolic conditions, neurodegenerative


disordersandmanymore.Dr.Mahajanhasfiled a patentforthetreatmentprocedureofAVN (Avascular Necrosis of Femoral Head) through regenerativemedicine (ApplicationNo:1369/MUM/2014) and also applied for international patent ‘Osteoinductive Formulation and Preparation Thereof’ (ApplicationNo:PCT/IN2015/000173).Other patents tohiscreditare :“How to treat Ankylosing Spondylitis?” and “How to develop IT-MSC technology (Ischemic tolerance MSC Treatment)?”.Hehasseveralresearchpublicationsinnationalandinternationaljournalsinregenerativemedicine.

Dr. Pradeep Mahajan has been credited national and international publications in clinicalresearchinregenerativemedicineandcellbasedtherapies.Dr.PradeepMahajanhaswritten and published a book on ‘Antidotes and Management of Chemical Poisoning’.

Heintroducednewtechnologywithminimalmanipulationofbonemarrowandadiposetissuestemcells.Withthistechnologyhetreated more than 2000 cases of various conditionswhichcouldnotbetreatedbyconventionalmethod.He quotes, “You carry your own repairing kits in your body”.Hebroughtthistechnologytocommonpeopleatthelowestcost.Dr.Mahajanwasinvitedtopresenthisworkonminimalmanipulationofbonemarrowandadiposetissuestemcellsforregenerativetherapy,toOhioStateUniversity,US.Therearemany cancer patients treated by cell based therapy under ‘Family Welfare Charitable Trust’ founded by Dr. P. V. Mahajan.

Dr.MahajanhasacademiccollaborationwithITMUniversity(Raipur)andMUHS(Nashik)aswellasOhio StateUniversity (USA) for different academic courseswith his organization- ‘StemRxBioscienceSolutionsPvt.Ltd.’He isalsoaggressive inresearchprojectswhereintheyarethecollaborativepartnerswithSanostem(USA),Stemedica(USA),AutostemPvtLtd(Chennai)andOhioStateUniversity(USA)fordifferentclinicaltrialsandresearchprogrammes.Withthevisionofservinghumanitybetterinthehealthcareindustry,hiscompanyStemRxBioscienceSolutionsPvt.Ltd.,hascomeupwithmultifacilityresearchcentrewithadvancedcellcultureandresearchlaboratoryestablishedwithworld class facilitiesatAndheri,Mumbai. This research facility isworkingunderhisguidanceonmolecularandcellularmedicine.

Dr.PradeepMahajanhastreatedworld’s youngest baby girlofage14 monthsforcerebral palsywithcellbasedtherapy.Hehasalsotohiscredit,achievementoftreatingworld’sfirstcaseandfirst person ofENS (Empty Nose Syndrome)usingregenerativemedicineandcellbasedtherapy.

Throughvarioussocialandhealthinformativeactivities,Dr.MahajanisveryactiveinarrangingCMEsinregenerativemedicine.Heisregularlyvisitedasaspeaker of ‘Hitguj’ – a Zee 24 Taas TV programmethroughwhichhesuccessfullysharestheknowledgeofregenerativemedicinetherapiesavailablefordifferentdiseasesforpublicandcommonmaneducation.Dr.P.V.MahajanregularlypublisheshisarticlesonstemcellclinicalresearchandregenerativemedicineinprintmediatocreateawarenessandIECamongcommonpeople.

Dr.PradeepMahajanhasperformedmore than 3500 charitable surgeriesinthelast 20 yearsatMathadi Charitable Hospital, Navi Mumbai.Hetookinitiativeinorganisingmorethan100healthcampsinassociationwiththeRotaryClubandalsoservedasCharterPresidentofRotaryClub,Airoli.Hehasconductedmanyhealthcampsforsocialorganizationsandpolicedepartment,vaccinationcampsandfirstaidtrainingprogrammes.


ProfileGENERAL PROFILE

ACADEMICS :

Qualification Board/ University/ Institute YearSSC NandedBoard March1977HSC NandedBoard March1979MBBS MarathwadaUniversity February1985MS MarathwadaUniversity February1988DU(DiplomainUrology) UniversityofVienna,Austria September1991AFIH LabourInstituteofCentral

Govt.,Sion2005

Laparoscopicsurgicaltrainingandcertificatecourse

KEMhospital,Mumbai 2005

ACADEMIC ACHIEVEMENTS :• TwotimesGOLDMEDALISTinMS(Surgery)fromMarathwadaUniversity.

• RecipientofLateShri.NarayanraoChitgopekarAwardforbestperformingcandidatein1987inMS(GeneralSurgery)exam.

TEACHING EXPERIENCE :• Hon. associate prof. of regenerativemedicine atH.B.T.M.C andDr. R.N. CooperGeneral

Hospital,Mumbai.

• Hon.associateprof.ofregenerativemedicineatMaharashtraUniversityofHealthSciences(MUHS),Nashik.

• Visitingfacultyatdept.ofregenerativemedicineandstemcells,OhioStateUniversity,US.

• Associateprof.ofsurgeryatTernaMedicalCollage,Nerulandminimalinvasivesurgery.

• Teachingexperienceaturologydept.,UniversityofVienna,Austria, inendourology,ESWLandminimuminvasivesurgery.

• Facultymemberforadvancediplomain industrialsafetycourseforoccupationaldiseasesandContinuousEducationProgramme(CEP)ofDirectorateofIndustrialSafetyandHealth(DISH)andThaneBelapurIndustriesAssociation(TBIA).

• ExaminerforMBBSatMUHS,Nashik.

• ProfessorforCPScourse.


TRAINING PROGRAMMES :• Tissueculture,OhioStateUniversity,USAforstemcelltherapy.

• Laparoscopicsurgerytrainingforoutsideoccupationhealthhazardandelectronicmanagement.

• Traininginantiagingcomprehensivemodule.

RESEARCH EXPERIENCE :• Creditedfornationalandinternationalpublicationsinclinicalresearchinregenerativemedicine

andcellbasedtherapies.

• Writingandpublishingofabook on ‘Antidotes and Management of Chemical Poisoning’.

• Throughanunexploredsubject ‘Nature Heals Through Nature’he isprovidinganalternativetotraditionalsurgerywithmultipledrugsusingtreatmentprotocolsofregenerativemedicinecellularbiology(stemcells).

• Introducednewtechnologywithminimalmanipulationofbonemarrowandadiposetissuestemcells.Withthistechnologyhehastreatedmorethan2000casesofvariousconditions,whichcouldnotbetreatedbyconventionalmethod.

• Dr.Mahajanwas invitedtoOhioStateUniversitytopresenthisworkonminimalmanipulationofbonemarrowandadiposetissuestemcellsforregenerativetherapy.

Research Papers And Articles Published

• PradeepV.Mahajan,AnuragP.Bandre,NitinS.Desai:

‘Study of cell therapy assisted regeneration of cartilage in avascular bone necrosis’D.Y.PatilJournalofHealthSciences,2014,2(1):41-45

• PradeepV.Mahajan,AnuragP.Bandre,NitinS.Desai:

‘Changing Paradigms in Healthcare Medicine’ IndianJournalOfStemCelltherapy,2014,1,50-53

• PradeepV.Mahajan,PrabhuMishra:

‘A novel cell based treatment for Avascular Necrosis of Femoral Head’(Acasereport)JournalofIndianOrthopaedicRheumatologyAssociation,2015,1(1),17-21

• PradeepV.Mahajan:

‘Role of Autologous Stem Cell Therapy in Relapsing Remitting Multiple Sclerosis’ (AcaseReport)

Articles/ Abstracts

• Evaluation of suture materialsin(surgical)wounds.

• AbstractinHealthScienceInnovationon‘RevampingofRegenerativeMedicine’,Jan2015


• Abstract inStemCellSocietyof IndiaandIndianFederationofNeuro-Rehabilitationon ‘StemcellnicheandTherapeuticApplicationofStemCells’,March2014

CURRENT ENGAGEMENTS : • ChairmanandManagingDirector,StemRxBioscienceSolutionsPvt.Ltd.

• Director,Dr.MahajanHospitalandIndustrialTraumaCentre,Rabale,NaviMumbai.

• Director,SidhharthMarineHealthServicesPvt.Ltd,Mumbai.

• Director,MEDI-CHECKHealthServicesPvt.Ltd.,Rabale,NaviMumbai.

• Hon.urosurgeonandconsultingsurgeonforMathadiTrustHospitalsince1993.

• MemberofboardofstudiesinITMUniversityRaipurforPhDcoursesinstemcellsandregenerativemedicine.

• Academic collaborationwith ITMUniversity (Raipur),MUHS (Nashik) andOhio StateUniversity(USA)fordifferentacademiccoursesintheareaofstemcellandregenerativemedicine.

• Consultantandpaneldoctor,shippingandlabourdepartment.

• ConsultingoccupationphysiciantoindustriesinThanedistrict.

AWARDS AND ACCOLADES• Dr.Mahajanhaswonseveralaccoladesforhisabstractsonhealthscienceinnovation‘Revamping of

Regenerative medicine’inJanuary2015andforanotherabstract‘Stem Cell Niche and Therapeutic Application of Stem Cells’, published in March 2014 in Stem Cell Society of India and Indian Federation of Neuro Rehabilitation.

• Dr.Mahajanhasbeenapartofseveralnationaland internationalconferences.Hehaspresentedseveral papers of international importance,suchasStem Cells for Orthopedic Condition,Therapeutic Application of Cancer Stem Cells and Cancer Stem Cells, Revamping of Regenerative medicine, Stem Cell Niche and Stem Cells Therapeutic Application and Therapeutic Application of Stem Cells.

• Dr. Mahajan has got numerous national and international recognitions for his research andinnovativeworkinthefieldofclinicalresearchinregenerativemedicineandcellbasedtherapy.Thisgothimthemostdignifiedappointmentofhonourary professor for regenerative medicine and cell based therapies in Cooper Hospital, Mumbai.

• Dr.Mahajanhasalsogainedaninternational reputationforhisresearch on cell therapy, assisted regeneration of cartilage in avascular bone necrosis.Hisresearch paper on ‘Changing Paradigms in Healthcare Medicine’waspublishedinthemostreputedIndian Journal of Stem Cell Therapy.

• HewasalsohonouredbytheGovernmentofIndiaandGovernmentofMaharashtrabyappointingasaconsultantandpaneldoctorwiththedirectorgeneralofshippingandlabourdepartment.


Awards

• Mrs. Mayadevi S. Darake Prize

• Gold Medal from Special ExecutiveMagistrates’ Society ofMumbai for Services in Trauma care on highway.

• Indian Achievers Award for Health Excellence, Delhi, for outstandingachievements in healthcare sector in India at 14th national seminar oncorporateachievementsandsocialresponsibilities.

• 2016 Leaders Awardfor‘FastestGrowingHealthcareBrandforStemCellTreatmentinMaharashtra’.

• Award at ITC Grand Central, ParelonJuly22,2016.


LANDMARK ACHIEVEMENTS• Carriedoutmorethan3500operations.

• Nearly2000operationprocedurescarriedoutatMathadiHospital,NaviMumbai.

• Successfullytreatedworld’syoungestcaseofCerebralPalsyinwhichtheageofthepatientwas14months.

• Treatedworld’sfirstcaseofENS(EmptyNoseSyndrome).

• Carriedoutmorethan500CMEprogrammestoeducatemedicalfraternityandpatientsbothalike.

• Dr.Mahajan’shospitalwasthefirst of its kind Industrial Trauma Care HospitaltobesetupinNavi Mumbai.

SOCIAL ACTIVITIES• Throughvarioussocialandhealthinformativeactivities,Dr.PradeepMahajanisveryactivein

arranging CMEsinregenerativemedicine.

• HeisalsoanactivememberoftheLocalCitiesCommittee,headedbytheCommissionerofNaviMumbai.Hiscampaign on HIV awareness for the industrial workershaswonhimseveralaccolades.

• Dr.PradeepMahajanhasperformedmorethan3500charitablesurgeriesinthelast20yearsatMathadiCharitableHospital,NaviMumbai.Hetookinitiativeinorganisingmore than 100 health campsinassociationwithRotaryClubandalsoserved asaCharter President of Rotary Club, Airoliandalsoconductedmanyhealthcampsforsocialorganization,policedepartment,vaccinationcamps,firstaidtrainingprogrammes.

• AsapracticingUrologicalsurgeonwithMathadiTrustHospitalinNaviMumbaiforthepast22years,hehasworkedforthewelfareofthepeople.

• He is currently the Charter President of Rotary Club of Airoli and an active member of Envirosafe Foundation of Safety, Health and Environment (SHE).

• HeisalsoanactivememberoftheLocalCitiesCommittee,headedbytheCommissionerofNaviMumbai.

• Duringhistenureasamedicalpractitioner,hehadorganizedmanyhealthcampsforsocialorganizations,policedepartmentsandhadbeeninstrumentalinorganizingseveralvaccinationcampstodoawaywiththedreadeddiseases.

• Inhis literarypursuit,Dr.Mahajanhasauthoredamedicalbook,namedas ‘AntidotesandManagementofChemicalPoisoning’.Hiscasereporttitled‘Neurogenicbladderrepairusingautologusmesenchymalstemcells’hasbeenconsideredforpublishing.


ASSOCIATE MEMBERSHIPS• TreasurerofSCSI.

• VicepresidentofAntiagingFoundation,Delhi.

• VicepresidentofSurgeons’CertifyingAssociationofMaharashtra.

• MemberofInternationalStemCellSociety,Singapore.

• Ex.memberofISCSG.

• MemberofIORA.

PATENTS• Nationalpatent for treatingAnkylosingSpondylitisandhowtodevelop IT-MSC (Ischemic

ToleranceMSCTreatment)

• Applied for – National patent for treatment procedures of AVN (AVascular Necrosis offemoralhead)

• Appliedfor–Internationalpatentforosteoinductiveformulationonpreparationthereof

KEYNOTE ADDRESSINTERNATIONAL CONFERENCE

• MesenchymalStemCells(MSC):ChangingParadigm,TheNewMedicineVIIand1stStemCellSocietyofIndia(SCSI)(June2016),Mumbai.

• ‘Stem Cells for Orthopedic Conditions (AVN)’ held by 1st Annual Conference of All IndiaOrthopedicSurgeonsCouncilatMadurai(September2015).

• ‘Therapeutic application of Cancer Stem Cells’ held byOhio State University, USA (August2015).

• ‘CancerStemCells’heldby1stAnnualConferenceofAllIndiaConferenceonRecentAdvancesinCancerManagement,atSymbiosis,Pune(June2015).

• ‘RevampingofRegenerativeMedicine’atHealthScienceInnovationConference,TajPalace,MumbaiheldbyOhioStateUniversity,USAandAllIndiaInstituteofMedicalSciences(January2015).

• ‘Stem Cell Niche and Stem Cells Therapeutic Application’ at (International association ofNeororestoratology)IANRVIIand1stStemCellSocietyofIndia(SCSI)with11thGCNNand2nd

(IndianFederationofNeuro-Rehabilitation)IFNRConference,Mumbai(March2014).

NATIONAL CONFERENCE

• ‘Therapeutic applicationof stem cells’ heldby StemCell Societyof India at IndiaHeritageCentre,NewDelhi(May2015).

• SmartLivingWorkshopon‘AntiAging’,organizedbySakethospital,NewDelhi,(August2013)MMCrecognizedCMEon‘Stemcelltechnologyanditsapplicationsinmedicine’organizedbyD.Y.PatilHospitalandResearchCenter,Nerul,NaviMumbai.(December2013).


Media coverage PRINT MEDIA

• The work done by Dr. Mahajan has received wide coverage in variety of national andinternational media including India Today, Asian Age, Telegraph, regional publications,NDTV(NewsChannel),DublinNews,IrelandandBrazilSun.

• Articleon‘StemCellscureMultipleSclerosis’inDublinNews,Irelandon18thFebruary2016.

• ArticleonstemcellsinIndiaTodayonFebruary2014.

• ArticleonstemcelltherapyinMaharashtraTimes,20thApril2016.

ELECTRONIC MEDIA

• Dr.MahajanisregularlyinvitedbyaleadingMarathiChannelZee24Taastosharehisviewsonthetopic-‘stemcelltherapyanditsapplication’.Itaddressesto

1. Stemcellsandtheirapplications.

2. Applicationsofstemcellsinthetreatmentofavascularnecrosis(AVN).

3. Applicationsofstemcellsinthetreatmentofdiabetes.

4. Stemcells:Majorremedyonuncurablediseases.

5. Roleofstemcellsinthetreatmentofbonediseases.

• AdocumentaryonNDTVtitled‘FutureofMedicine’featuringtheresearchhasbeentelecast.


IOSRJournalofDentalandMedicalSciences(IOSR-JDMS)e-ISSN:2279-0853,p-ISSN:2279-0861.Volume15,Issue4Ver.1(Apr.2016),PP127-130www.iosrjournals.org

Role of Autologous Stem Cell Therapy in Relapsing Remitting Multiple Sclerosis: A Case Report

Dr. P. V. Mahajan1, Dr. Swetha Subramanian2, Mr. Anurag Bandre3, Dr. Anand Kumar4 1CMD,StemRxBioscienceSolutionsPvt.Ltd.,Rabale,NaviMumbai

2ClinicalAssistant,StemRxBioscienceSolutionsPvt.Ltd.,Rabale,NaviMumbai3Manager(LabOperations),StemRxBioscienceSolutionsPvt.Ltd.,Rabale,NaviMumbai4Director(LabOperations),StemRxBioscienceSolutionsPvt.Ltd.,Rabale,NaviMumbai

ABSTRACT: Multiple sclerosis is a progressive disease characterized by accumulating disability. Although advances in

conventional treatment have been made to reduce the relapse rate, these modalities do little in terms of repair to the damaged CNS. Cellular therapy represents a promising approach in management of neurological conditions associated with morbid outcomes. Mesenchymal stem cells (MSC) foster repair of the CNS through tissue integration and differentiation into neural cells. Additionally, through mechanisms of neuroprotection and immunomodulation, MSCs may be effective in the treatment of multiple sclerosis. This report presents a case of relapsing remitting multiple sclerosis treated with autologous stem cells.

Keywords: Multiple sclerosis, Mesenchymal stem cells, Platelet rich plasma

INTRODUCTION:

Multiplesclerosis(MS)isconsideredasanimmune-mediateddiseaseassociatedwithimmuneactivitydirectedagainstcentralnervoussystemantigensthatfrequentlyleadstoseverephysicalandcognitiveimpairment.StructureswithinthenervoussystemdamagedinMSincludemyelin,oligodendrocytesandunderlyingnervefibers.

MShasbeenreportedtoaffectmorethan2millionpeopleworldwideandisconsideredthemostcommonnon-traumaticcauseofdisabilityinyoung(<50years)Europeanadults[1].MShastwodistinctclinicalphasescorrespondingtointer-relatedpathologicalprocesses:focalinflammationthatdrivesactivityduringtherelapse-remittingstageandneurodegenerationthatunderliesprogressivediseasecharacterizedbyaccumulatingfixeddisability[2].

Histologically, active lesions are characterized by presence of macrophages containing fragments of myelin.Perivascular inflammatory infiltratemostly composedof T-lymphocytes, reactiveastrocytosis andmicroglial cellsarealsoseen.Oligodendrocytesareusuallypreservedorslightlyreducedinnewlydemyelinatinglesions.Chronicinactiveplaquesareassociatedwithdensefibrillarygliosis,lossofoligodendrocytes,fewmicroglialcellsandmarkedreductionofaxonaldensity[3].

MSCs may be effective in treatment of multiple sclerosis through mechanisms of neuroprotection,immunomodulationandneuroregeneration[4].ThesepropertiesmayaidinreducingdamageinthecentralnervoussystemofMSpatients,whichresultsfromimbalancebetweenthedeleteriousimmuneresponseandfailureoftheremyelinatingmechanisms.

Thefollowingreportdescribesautologousstemcelltherapyalongwithplateletrichplasmaadministrationinapatientwithknownhistoryofmultiplesclerosisunresponsivetostandardtherapy.

CASE REPORT:A19yearoldmalepatientreportedtoStemRxBioscienceSolutionsPvt.Ltd.withthecomplaintsofrecurringgait

disturbancesandinabilitytoperformdailyactivitieseffectively.

Medicalhistoryrevealedthathefirstexperiencedlossofconsciousnesswhileplayingonagroundbefore4years.Hewasunabletolifthislegthereafterandconsultedalocalphysicianforthesameforwhichhewasgivenmedicationforabriefperiod.Sixmonthslater,thepatientwasadmittedtoahospitalwiththecomplaintofheavinessinhisrightlegandgaitdisturbance.BloodandradiologicalinvestigationsweredoneandMRIrevealedthatthepatientsufferedfromMultipleSclerosis.Hewasundersteroidmedicationfor3monthsandthesymptomswerebroughtundercontrol.Overthecourseofthefollowingyear,thepatientrepeatedlyhadthepreviouslymentionedcomplaintsinadditiontouncontrolledmovementsoftheneck,inabilitytowrite,talkclearlyandurineincontinence.Steroidtherapywasadvisedwhichtemporarilyrelievedthesymptoms,however,thepatientgraduallystoppedrespondingtothemedications(inabout2yearsafterthetherapywasinitiated).Thereafter,immuno-modulatorytherapywith


beta-interferonwasgivenfor6monthsfollowedbyalternativemedicinemodalitiesfor1-1.5years,noneprovidinganyimprovementofsymptoms.InJuly2014,thepatientwasbedriddenfollowinganepisodeoffeverandgeneralweakness.

Onthefirstvisitofthepatient,completeradiologicalandhematologicalinvestigationsweredone.HematologicalassessmentdidnotrevealanyabnormalitieswiththeexceptionofpositiveC-reactiveproteinlevel.ThepositivelevelindicatesthatCNSinflammatoryresponseinMSisdependentontheperipheralimmunecompartment[5].Fig.1a&1bshowtheMRIimagestakenbeforeandafterinitiationofconventionaltreatment.ClinicalassessmentcriteriahavebeenpresentedinTable1.

A final diagnosis of Recurrent Relapsing Multiple Sclerosis was made. The relapsing-remitting subtype ischaracterizedbyunpredictablerelapsesfollowedbyperiodofmonthstoyearsofrelativeremissionwithnonewsignsofdiseaseactivity.

STEM CELL THERAPY: Threesessionsofstemcell therapywithan intervalof15daysbetweenevery twoconsecutivesessionswas

plannedforthepatientduringhisinitialstayatthehospital.Followupwasdoneafter3monthsduringwhichtwomoresessionsofcellulartherapywereadvised.Approximately100ml.ofbonemarrowfromtherightiliaccrest,70-80ml.ofadiposetissuefromrightglutealregionwasaspiratedunderlocalanesthesia.50ml.ofperipheralbloodwasobtainedfromrightcubitalvein.

Stemcelltransplantationwasdonebyintrathecal,intravenousandintranasalroutes.Inaddition,intravenousdoseofPRP,whichisaplateletconcentrateandareservoirofgrowthfactorswasadministered.Physiotherapyexercises,neuromuscularstimulation,yoga,nutraceuticalsandabalanceddietspecificforthepatient’sconditionwereadvised.

RESULTS:Clinically,positiveeffectof treatmentwasdefinedasAdecrease inEDSSof1.0pointorgreatercomparedwithbaseline.Theresponsetocellulartherapyprovidedwasseenduringthefirstfollowupperiod.Thepatientregainedsomeofhisabilities toperformroutineactivitieswithassistance.Graph1showsthe improvement in functionalsystemscoresfollowingcellulartherapy.Theimprovementnoticedinindividualfunctionalsystemwasgradual,butthatwasconsideredapositiveeffectonourpartasthepatientwasbedriddenwhenhefirstreportedtothehospital.

Fig. 1c shows the resolutionof lesions in periventricular region in theMRI takenone year after the cellulartherapy.However,threetinyfociofrestricteddiffusioninvolvingbilateralfrontalsubcorticalwhitematterregionandleftperirolandicsubcorticalfronto-parietalwhitematterregionswereobserved.Nonetheless,thisisconsideredanimprovementincomparisontothepreviousextentoflesions,andperiodicmonitoringwillbedonetoassessanyfurtherchangesandplantreatmentifneededatalaterstage.

Itwasobservedthatthepatientcouldwalkonhisownwithoccasionalsupport.Significantimprovementingaitwasnoticed.Heisnowabletoperformdailyactivitiesbyhimselfwhichwasnotpossiblebeforetreatment.

DISCUSSION Conventionaltherapiesformultiplesclerosisusingimmunosuppressants,monoclonalantibodiesetc.effectively

reduceinflammation;butdo little intermsofrepairtothedamagedcentralnervoussystem[6].Treatmentwithbeta-interferonswasconsideredasamajoradvancementinthetreatmentofthisdiscase;however,theireffectisstilllimited[7].

ThehypothesisoftheuseofautologousstemcelltherapyisbasedonthetheorythatenvironmentalfactorsplayanimportantroleinthepathogenesisofMSandthatthetherapycouldbeusedtoresettheautoimmunecelllinetherebyrestoringself-tolerance[8].BM-MSCcanpromoteneuroprotectionbyinhibitinggliosis,scarformationandapoptosis,andbystimulatinglocalprogenitorcells.Itisalsopossiblethatthesecellsmaydifferentiateintoneuralcellsandcontributetocellreplacement.

Stromal vascular fraction (SVF) derived from adipose tissue has been shown to containmesenchymal stemcells (MSC), endothelial precursor cells, preadipocytes as well as anti-inflammatoryM2macrophages [9]. MSCcompartment fromSVF inhibit innate immuneactivationbyblockingdendriticcellmaturationandsubsequentlysuppressadaptiveimmunitybygeneratingTregulatory(Treg)cellsandblockingcytotoxicactivitiesofCD8cells.

Inthisreport,weobservedanimprovementinclinicalparameters,theresultsofwhicharebeingmaintained.ThisisconsistentwithfindingsreportedbyYamoutetal.(2010)whostatedthatearlysignsofclinicalimprovementfollowingBM-MSCtransplantareseeninmostpatientsby3monthsandmaintainedupto1year[10].Also,Liangetal.(2009)reporteddecreaseinEDSSofatleast2pointsfromthebaselineof8.5,inafemalepatientdiagnosedwithprimaryprogressiveMS,whichwasconfirmedduring2monthsafter transplantationofallogeneicmesenchymalstemcells [11]. These reportsalongwithourfindings support theeffectivenessof stemcell therapy inmultiple


sclerosis.ThiscouldbeattributedtothepotentialformigrationofmesenchymalstemcellsintoinflamedCNStissueanddifferentiationintocellsexpressingneuronalandglialcellmarkers.

Researchershavestatedthatmyelinrepaircanhappenwithoutinduction,probablyduetoactivationofprogenitoroligodendrocytes,causingspontaneousremyelination.IthasalsobeenfoundthatPDGFplaysanimportantroleinmultiplicationandgrowthoftheseprogenitorcells[12].TheadministrationofPRPinthispatientensuredthatanincreasednumberofgrowthfactorssuchas,PDGF,VEGF,TGF-beta,EGF,FGF,IGF-1wasdeliveredtothesurgicalarea.PRPsecrete70%ofthestoredgrowthfactorswithin10minutesandcloseto100%withinthefirsthour.Thereafteradditionalamountsofgrowthfactorsaresynthesizedupto8daysfollowingwhichtheplateletsdie[13].

Additionally,BrainDerivedNeurotrophicFactor(BDNF),whichisamemberoftheneurotrophinfamilyofgrowthfactors,hasbeenshowntoenhanceCNSmyelinalionduringdevelopment.BDNFalsoexertsneuroprotectiverolesfollowingdemyelinationinanimalmodelsofMS[14].DeficientBDNFinT-cellsresultedinprogressivedisabilityandenhancedaxonalloss;whileoverexpressionofBDNfpresentedwithlessseverediseaseandaxonalprotection[15].WeadministeredBDNFdropsorallyasasupportivemodalitytoenhancemyelination.

Thegoalofdietmodificationsandneuromuscularrehabilitationinmultiplesclerosisistoreducetheoxidativestressandaid instrengthmaintenance.Forthispurpose,aglutenfreedietwasadvisedwithadequate intakeofprotein rich foods, cruciferous vegetables and citrus fruits. Antioxidant supplementswere prescribed to furtherachieveimprovedoutcomesfollowingthetreatment.Agradualimprovementinstrengthandenduranceofmusclegroupswasnoticed4-5monthsaftertheaboveprotocolwasinitiated.

CONCLUSION: The purpose of cellular therapy done forMS is to slow the progression of the disease,minimize symptoms

duringexacerbationsandtoimprovephysicalandmentalfunctions.TheinjectionofMSCwasnotassociatedwithanyadversereactioninthispatient;andresultedinimprovementofclinicalparametersalongwithlimitingdiseaseprogression.Nevertheless,furtherlongtermfollowupisessentialtoassessthemaintenanceofresults.Also,furthertrialsarenecessarytodeterminetherequiredcellulardose,numberofinjections,timingofinjections,determiningthebestcellsubtypes(amongstemcellpopulation)toachieveoptimumresultsinpatientswithmultiplesclerosisaswellasotherautoimmuneconditions.

REFERENCES:[1] PugliattiM.RosatiG.CartonH,etal.TheepidemiologyofmultiplesclerosisinEurope,EurJNeurol,13,2006,700-22.

[2] CompstonA,ColesA,Multiplesclerosis,Lancet,372,2008,1502-17.

[3] RoncaroliF,NeuropathologyofMultipleSclerosis,ACNR,5(2),2005.

[4] UccelliAandMancardiG,CurrOpinNeuro,23(3),2010,218-25.

[5] Soilu-HanninenM,KoskinenJ.O.,LaaksonenM,HanninenALiliusE-M,WarisM,HighsensitivitymeasurementofCRPanddiseaseprogressioninmultiplesclerosis,Neurology,2005.

[6] WiendlHandHohlfeldR,Multiplcsclerosistherapeuticsunexpectedoutcomescloudingundisputedsuccesses,Neurology,72(11),20009,1008-1015.

[7] VosoughiRandFreedmanSM,Casereport:Multiplesclerosisandamyotrophiclateralsclerosis,InternationaljournalofMScare,12(3),2010,142-145.

[8] VanBekkumDW,Stemcelltransplantationinexperimentalmodelsautoimmunediseases,JClinlmmuno,20,2010,10-6.

[9] NeilHRiordan,ThomasElehim,Wei-PingMin,HaoWang,FabioSolano,FabianLaraetal,Nonexpandedadiposestromalvascularfractioncelltheraphyformultiplesclerosis,JournalofTranslationalMedicine,7,2009,29.

[10] BassemYamouta,RoulaHourani,HaythamSaiti,WissamBarada,TaghridEl-Hajj,AghiadAl-Kutoubietal,Bonemarrowmesenchymalstemcelltransplantationinpatientswithmultiplesclerosis:Apilotstudy,J.Neuroimmunol,2010.

[11] JLiang,HZhang,BHua,HWang,JWang,ZHanandLSun,Allogeneicmesenchymalstemcellstransplantationintreatmentofmultiplesclerosis,Multiplesclerosis,15,2009,644-646.

[12] Woodruff RH., Fruttiger M., Richardson WD, Franklin RJ. Platelet-derived growth factor regulates oligodendrocyteprogenitornumbersinadultCNSandtheirresponsefollowingCNSdemyelination,MolCellNeurosci,25,2004,252-62.

[13] Robert,E.Marx,Platelet-richplasma(PRP):WhatisPRPandwhatisnotPRP,Implantdentistry,10(4),2001.

[14] XiaoJ.WongAW,WillinghamMM,vandenBuuseM,KilpatrickTJ.etal,Brain-DerivedNeurotrophicFactorPromotesCentralNervousSystemMyelinationviaaDirectEffectuponOligodendrocytes,Neurosignals,18,2010,186-202.

[15] LinkerRA,LeeDH.,DemirS.,WieseS,KruseN.etal,Functionalroleorbrain-derivedneurotrophicfactorininneuroprotectiveautoimmunity:therapeuticimplicationsinamodelofmultiplesclerosis,Brain133,2010,2248-2263.


A novel cell based treatment for Avascular Necrosis of femoral head: A case report

Pradeep V. Mahajan1*, Prabhu Mishra, Manish Khanna, Anurag Bandre, Swetha Subramanian, Manu Menon, Nitin Desai2*

1ChairmanandManagingDirector,StemRxBioscienceSolutionsPvt.Ltd.R-831,T.T.C.,ThaneBelapurRoad,Rabale,NaviMumbai,Maharashtra,India

2AmityUniversity,Mumbai,Maharashtra,India

*Corresponding Author: Email:[email protected]/[email protected]

ABSTRACT: Avascular necrosis (AVN) of femoral head is a progressive disease characterized by a vascular insult to the

blood supply of the femoral head, which can lead to collapse of the femoral head and subsequent degenerative changes. The femoral head, carpals, humerus are the most commonly affected bones. Regenerative medicine - a branch of translational research, uses cell based therapies in tissue engineering which deals with the process of re-engineering or regenerating human cells, tissues or organs at the defective sites to restore or establish normal function. On the basis of the concept of regenerating cells we present a case that deals with the treatment of avascular necrosis of femoral head in a 35 year old male patient with cell based therapy.

INTRODUCTION: Thehealthcaresectornowisnotjustlimitedtotheconceptoforganreplacementbuthasshiftedtothe

conceptoforganregeneration;andcellbasedtherapieshaveplayedanimportantrole inthisparadigmshift.Cellbasedtherapiesarebasedontheapplicationofstemcellswhicharedifferentiatingandimmunomodulatory.Avascularnecrosisisaconditionthatoccursduetodisruptionofbloodsupplytothebonewhichultimatelyleadstocollapseofthebone.TheconventionaltreatmentofAVNmaybenon-operativeand/oroperative.Non-operativetreatmentmodalities include elimination of causative factors, use of anti-osteoporotic agents (bisphosphon-ates ere), analgesics, non-weight bearing exercises etc. Operative treatment includes core decompression,jointpreservationandreplacement (totalorpartial)procedures.However, the resultsof theaforementionedtreatmentmodalitieshavebeenunsatisfactory.TheextentandthelocationofthelesioninvolvingthefemoralheaddeterminestheprognosisofAVN.Ohzonoetal.reportedthatthelesionsinvolvingthelateralonethirdoftheweightbearingareaordiffusefemoralheadinvolvementhadmorethan90%chanceofcollapse[1].Leeetal.statedthattheoverallcollapserateofAVN(hips)was78%within2years[2].InacasestudyonAVNofthehipjoint,Steinbergetal.reportedthat92%ofcasesprogressedtocollapsewhenmanagedwithnon-operativetreatment[3].

TheuseofautologousstemcellshasshownpromiseinhaltingtheprogressionofAVNofthefemoralheadandsubsequentlypreventingyoungpatientsfromundergoingtotalhiparthroplasty[4].Animalexperimentshavedemonstrated thepotentialof stemcells topromoteneovascularizationwhicheffectively increase thebloodperfusion inananoxicenvironmentandthus inhibit furthernecrosisoftissues [4,5].Thus, transplantationofmesenchymalstemcellsmaybeaminimallyinvasivestrategyforthetreatmentoffemoralheadnecrosis.

In 2002, Hernigou and Beaujean first described a technique for injecting mesenchymal stem cellscombinedwithstandardcoredecompressiontointroducebiologiesintoanareaofnecrosis[6].Thisstudywasdonein116patientsusingautologousmesenchymalstemcellsandin5yearsclinicalfollowup,promisingresultswereobserved for thepatientsofgrade IIAVNwhere theprogressionof thediseasewasstopped [7].Thus,transplantationofmesenchymalstemcellsmaybeaminimally invasivestrategyforthetreatmentoffemoralheadnecrosis.

Inthiscasereport,wedescribethetreatmentofavascularnecrosisofthefemoralheadwithbonemarrowandplateletconcentrate.

CASE REPORT:A35yearoldmalepatientcametoourhospitalwithcomplaintofpaininlefthipjointsince10years.The

patienthadintermittentpainradiatingtohisrightgroinandantero-medialthighregion.Healsocomplainedofrestrictedhipmovementswithstiffnessandmildpaininthelowerback.Historyrevealedthatthepatienthadafallfromstairs15yearsago.Nootherrelevantmedical/surgicalhistorywasreportedbythepatient.Thepatienthadconsultedanorthopedicsurgeonwhoprescribedpainkillersandnutritionalsupplements.However,relieffromsymptomswasminimalandtemporary.


On the patient’s first visit to our hospital,complete clinical, hematological and radiologicalinvestigations were done. Clinical scoring of thepatient’s condition was done based on Harris HipScore.Atotalscoreof28(poor)wascalculatedbasedonrangeofmotionscoresandthefindingsofmarkedpain,moderate limp, useof 2 canes/crutches, abilityto sitonahigh chair for30minutes, inabllity toputonshoes/socksandenterpublictransportation.Table1showstherangeofmotionvalues:

Table1:degreeofmovement

FLEXION: 40degreesABDUCTlON: 10degreesADDUCTION: 10degreesEXT.ROTATION: 5degreesINT.ROTATION: 8degrees

Radiological investigations [X-ray (Fig 1) and MRI(Fig2)]revealed:

• Marrowoedema in left femoralhead, leftacetabulum,

• Small erosions in the acetabulum andfemoralarticularmargins,

• Thinningofarticularcartilageandreductioninjointspacewithsynovialthickening.

A.P.viewofpelviswithbothhipjointsrevealthalleftfemoralheadshowscorticalirregularityofarticularsurface with gross narrowing of left hip jointspace.Theneckandthecorticalheadstructureismaintainedinspiteofirregularerosionasdescribedearlier.Osteopeniaisvisualized.AbovefindingsaresuggestiveofAVNofleftfemoralhead.

Figure 1: XRAY of both hip joints showing AVN affected femoral head area (circled) dated 03-02-20I4


Figure 2: MRl of the hip joint confirming AVN of the femoral head dated 03-02-2014

Basedontheassessment,finaldiagnosisofAvascularnecrosisoftheleftfemoralhead(StageIIasperFICATandARLETclassification)wasconfirmed.

CLINICAL METHODOLOGY & TREATMENT PLAN:

On the basis of clinical findings the patientwas admitted for treatment in March 2014 and apersonalized treatmentprotocolwasmadebasedontheseverityoftheconditionandgeneralfactorssuchasageofthepatient,bodymassindexetc.Theprotocolinvolvedharvestingbonemarrowconcentrate,stromalvascularfraction(SVF)fromadiposetissueandplateletrichplasma(PRP)fromperipheralblood.

Bone marrow concentrate contains mixedpopulation of progenitor cells comprising ofmesenchymal and hematopoietic cells along withmononuclear cells. Stromal vascular fraction isolatedfrom adipose tissue consists of endothelial cells,adipocyte progenitors, immune cells, fibroblasts,pericytes and stromal cells. Platelet rich plasma is aplateletconcentrateanda reservoirofcytokinesandgrowth factors. Vascular endothelial growth factor(VEGF),fibroblastgrowthfactor(FGF),plateletderivedgrowth factor (PDGF), transforming growth factor(TGF-β).insulin-likegrowthfactor(lGF)andepidermalgrowth factor (EGF) that are present in PRP play animportantroleinthehealingprocess.Transplantationdose was calculated on the basis of cell count andgradeofthedisease.


RESULTS:

Following treatment, the patient was kept underobservation for 48 hours at the hospital. This wasa non-interventional period for homing of the cellsand for monitoring the general condition of thepatient. Thepatientwasadvisednonweightbearingphysiotherapy exercises (passive) such as stretchingofthehamstrings,hipflexorsandabductorsfollowedby range of motion exercises for the hip and knee.Strengthening exercises were gradually instructed tostrengthenprimarilythequadriceps,hipabductorsandhamstringsmusculature.Thepatientwasinstructedtocontinue the rehabilitationexerciseprogramme for1year.

Follow-up was done periodically wherein clinicaland radiologjcal assessment was done. The patientshowedgradualimprovementinclinicalparametersofpainandmovements.Harrishipscorecalculationwasdoneatthe3rd,6thand12thmonthfollow-up.Attheendofthefirstyear,thescorewas89(good).Thepatientwasfreeofpainwithin6monthsaftertreatment.Thepatientisnowabletowalkunlimiteddistancewithoutusingcane/crutches,cansitcomfortablyonanychair

andisabletoenterpublictransportation.

Figure 3: One year post operative X-ray of the hip joints dated 05/03/2015

CLINICAL LMPRESSION OF THE RESULT:

A.P view of pelvis with both hip joints revealsright hip joint as normal and left hip joint showingimprovement in joint space (circled area) comparedto the pretreatment X-ray. The conical irregularityof the articular surface of the femoral head showsimprovement.Osteopeniaisvisualized.

IMPRESSION:

Reductionincorticalirregularitynoted.

DISCUSSION:

The commoncauses implicated in theetiologyofavascularnecrosisofbonearecorticosteroiduseandtraumawhichresultsininterruptionofbloodsupplytotheareathusleadingtonecrosisofthebone.TheothercausesofAVNmaybesystemic lupuserythematosus(SLE), pancreatitis, alcoholism, gout, radiation, sicklecell disease and infiltrative diseases (e.g. Gaucher’sdisease).

The occurrence of AVN among younger adults,use of prosthesis and risk of surgery limit theapplicationofconventionaltreatmentmodalitiessuchas arthroplasty, core decompression etc. Cell basedtherapyisthusgainingpopularityasanon/minimallyinvasive therapeutic modality in the treatment ofvarious disorders. The unique properties of stemcells namely differentiation potential, self renewal,anti-inflammation and immune-modulation aid inregeneration of structures/tissues rather than repairwhich commonly occurs after conventional/surgicaltreatmentmodalities.

Inourstudy,thecauseofAVNwastraumaticinjury,which possibly remained undetected in the initialphase.Afterundergoingcellbasedtherapy,thepatientshowed gradual improvement with each follow-upwhichreaffirmsthepositiveeffectofcellbasedtherapyincasesofavascularnecrosisorfemoralhead.

Homing of stem cells is a complicated processwhichinvolvesanarrayofmolecules.Necrosisofcellsinducesthereleaseofaseriesofsignalingmolecules,inwhichspecificreceptorsorligandsexpressedininjuredtissues play an important role. Vascular endothelialcells express a variety of adhesion molecules. Stemcellsarecapableofadheringtotheseendothelialcellsand reach the site of ischemia. Studies have shownthatmesenchymalstemcellscannotonlymigrateintothefemoralhead,butalsoremainintheregionforarelativelylongtime.

The route of administration of cells also plays animportantroleinthedegreeofimprovementachieved.In our study, the patient was administered intra-articularandintravenousdosesofmesenchymalstemcells. In a study by Zhang-Hua Li et al., intravenousadministrationofcellsresultedindirectionalmigrationofthecellstofemoralheadstosurviveinthenecroticenvironment. The rationale behind intra-articularadministrationwastoachievehigherconcentrationofcellsinthelocalizedarea.Nevertheless,furtherstudies


should be done to study the directional migrationof stem cells in order to formulate more specifictreatmentprotocols.

CONCLUSION:

Thiscasereporthighlightsthepositiveoutcomeofcellular therapy achieved in a patientwith avascularnecrosis of the femoral head. The patientwithstoodtheprocess fairlywellwithnoobviouscomplicationsoradversereactions.Theresultsarebeingmaintained(after1year)andhasalsoresultedinanimprovementintheoverallqualityoflifeofthepatient.

REFERENCES:

1. Ohzono K, Saito M, Sugano N, Takaoka K, OnoK. The fate of nontraumatic avascular necrosisof the femoral head. A radiologic classificationto formulate prognosis. Clin Orthop Relate Res1992;277:73-8.

2. LeeMS, Chan YH, Chao EK, Shih CH. Conditionsbefore collapse of the contralateral hip inosteonecrosis of the femoral head. Chang GungMedJ2002;25:228-37.

3. Steinberg ME, Hayken GD, Steinberg DR. The

‘conservative’managementof avascularnecrosisofthefemoralhead.In:ArletJ,FicatPR,HurgerfordDS,eds,Bonecirculation,Baltimore:WilliamsandWilkins;1984:334-7.

4. Tateishi-Yuyama E, Matsubara H, Murobara T,et al. Therapeutic angiogenesis for patientswithlimb ischaemia by autologous tranplantationof bone-marrow cells: a pilot study and arandomized controlled trial, Lancet. 2002 Aug.10;360(9331):427-35

5. lkenagaS,HamanoK,NishidaM,etal.Autologousbonemarrow implantation inducedangiogenesisand improved deteriorated exercise capacityin a rat ischemic hindlimb model. J Surg Res,2001,96(2):217-283

6. HerndonJH,AufraneOE.Avascularnecrosisofthefemoralheadintheadult.Areviewofitsincidencein a varietyof conditions. ClinOrthopRelatRes:1972;86:43-62.

7. HemigouP.BeaujeanF,Treatmentofosteonecrosiswith autologous bone marrow grafting. ClinOrthopRelatRes.2002;405:14-23.


RESEARCHPAPER

A study of Cell Therapy Assisted Regeneration of Cartilage in Avascular Bone Necrosis.

Mahajan P. V., Bandre A.P., Desai N. S. ABSTRACT:

Application of ‘regenerative medicine’ hasgiven a new hope to surgeons for the treatmentof several chronic diseases and disorders includingsevere orthopedic conditions. There are amyriad oforthopedicconditionsandinjuriesthatpresentlyhavelimitedtherapeutictreatmentsandcouldbenefitfromnew developing therapies in regenerative medicinewith the help of stem cells[1]. Regenerativemedicinetherapies are mainly based on the applications ofstem cells. Stem cells play a vital role in orthopedictreatments and the studies have shown promisingresults in repair of bones, tendons, cartilages etc.Bone and cartilage regeneration ability of stem cellshas been demonstrated clinically; however successratemay not be same in every case and it dependson patient. Several factors can be responsible forthe same; including patient’s immune response, thetype and the grade of the disease which altogetherdecide the fate of the treatment. In this paper, wehavepresented someof the orthopedic case studiesperformedthroughautologoustransplantationoftheStemcells.

Keywords: AVN (Avascular Bone Necrosis), ECM(Extracellular Matrix), cytokines and chemokines,bonemarrowmononuclear cells,adiposetissue,PRP(Plateletrichplasma)

INTRODUCTION:

Stem cells- known as the building blocks of thebody- represent unspeciallzed cells, which have theabilitytodifferentiateintodifferenttypesofadultstemcells. Thedifferentiationdepends on the typeof thestem cell and the niche. Niche and several signalingpathwaysareresponsibleforthedifferentiationofthestemcellsintoparticularlineageofthecell[2,3].Broadly,stem cells are classified as ‘embryonic’ and ‘adult’stem cells. Being truly pluripotent, embryonic stemcells(ESC)canrenewindefinitelyanddifferentiateintocells of all three germ layers thereby can regenerateapartorevenacompleteorgan[2.3].Embryonicstemcells are not easy to harvest and havemany ethicaland legal issues associated so attemptswere startedtoinducepluripotencyinsomaticcellstomakethemfunction like ESC’s. Takahashi and Yamanaka in 2006firstreponedtheconceptofinducedpluripotentstemcells(iPScells)[4].

However because of the teratogenic potential

of induced pluripotent stem cells, the technique isyet in the frameofquestionmark for its commercialuseinthemass[5,6].However, incontrast,avarietyofmultipotentadultstemcellsexistinalmostalltissuesof the organisms which reside in a specific niche invivo where various microenvironmental cues forman intertwined signaling regulatory network thatmaintainsstemcells’ fateandfunctions. Inthisnichethere are different regulators such as ECM (ExtraCellularMatrix)molecules, biochemical cues such assolublegrowth factorsandcytokinesandmechanicalcues such as intrinsic matrix stiffness and extrinsicforceswhichplayamajorrole indecidingthefateofthestemcell.

Multipotent adult stem cells derived from bonemarrow also known as mesenchymal stem cellsare considered as the most competent stem cells.These MSCs can be induced in vitro and in vivo todifferentiate into a variety of cell lineages includingbones,cartilages, tendons,musclesandothersimilartissues[7]. However their differentiation into othertypesoftissue-specificcells,suchascardiacmyoblasts,endothelialcells,hepatocytesandneuralcellshasalsobeendemonstratedinexperimentalstudies[8,9].

STEM CELLS IN THE TREATMENT OF ORTHOPEDIC CONDITIONS:

Mesenchymal stem cells derived from bonemarrowareabletodifferentiateintodifferentlineagesas they come in contact with specific niches. MSCsareknowntobecapableofosteogenic,chondrogenicdifferentiation. Bone marrow is aspirated from theregion of posterior superior iliac spine and the stemcellsareisolatedandprocessedtopreparethedoseforthe transplantation[10].Modern day orthopedics withtheuseofcellularmedicineforrejuvenariontherapieslooks promising and has overcome the traditionalsurgical therapies. Traditional replacement therapiesinvolve the use of artificial joints with invasiveoperativeprocedureswhich take longertime tohealproperly. There are numerous problems associatedwith the use of biological grafts including donor sitemorbidity,scarcityandtissuerejection.Thesetypesofproblemscanbesolvedbyusingstemcell transplantas they are based on less invasive applications ofcellular medicine. Most of the orthopedic problemsare because of degeneration of cartilage. When wetransplantmesenchymalstemcellslocally,thesecells


try to move in the micro-environment of the bonesand tend to convert into osteogenic, chondrogeniccells[11].Thesecellshelpinregeneratingthedamagedarea by forming new hyaline cartilage and bone. InNon-unions, avascularnecrosis (AVN),bone fracturesandbonedefects,tendinitisandcartilagedefects,stemcellsandregenerativemedicinehaveadefiniterole.

BONE FRACTURES:

Bone has a natural tendency to reform whenfractured or damaged and while doing so it mayshow development of fibrous cartilage.MSCs havingosteogenic potential tend to differentiate along theosteogenic pathway in response to the niche factorsstimulation. Niche is usually composed of growthregulators, cell adhesion molecules, niche cells andextra cellular matrix which govern differentiation ofstem cells[11, 12]. The process of entire regenerationof bone at thedamaged site after the applicationofthe stemcells canbedependenton factors likeareaof dislocation or grade of the fracture. The cellularmedicinewiththeuseofgraftswasstudiedbyFernandezClal. to study theeffectofautologousbonemarrowmononuclearcells(BM-MNCs)onpseudarthrosis.TheyconcludedthatbycouplingautologousBM-MNCsandallogenicbonegraftonecouldconstituteaneasy,safe,inexpensiveandefficaciousattempttotreatlong-bonepseudoanhrosis[13].Thesestudiesshowedhowstemcells arehelpful in promotingunion in casesof non-unionswhentheyareusedaloneorincombination.

STEM CELLS IN THE TREATMENT OF AVASCULAR NECROSIS OF FEMORAL HEAD AND BENY GAPS:

Avascular necrosis (AVN) of femoral head is apathologicalprocessthatresults from interruptionofblood supply to the bone. Loss of vascularitymeansthe blood supply for these bones enters throughvery restricted spaces & there is limited collateralcirculation which ultimately leads to death ofosteoeytcsandcollapseoffemoralheadwithchangeintheshapeoffemoralheadassociatedwithpain,limpandrestrictionofmovements[14].Therateofavascularnecrosis of femoral head is found higher in youngpatients following trauma, steroid intake, alcoholconsumption etc. Treatment options available tilldateprimarily focussedonreducing the intraosseouspressurebydrillingchannelsintotheheadthroughtheneck. In advanced disease, replacement arthroplastyis commonly opted; but new surgeons are lookingforwardtocellularmedicineasaneffectivetreatmentover traditional surgical procedures. Recently, Wanget al. concluded bone marrow mononuclear cellsimplantation as an effective procedure in patients

withearly-stageAVNoffemoralhead[15].Theadditiveapplication of concentrated bone marrow aspirates,ex vivo expandedmesenchymalstemcells,holdsgreatpotential to improve bone regeneration[16]. Similarlyusingautologousmesenchymal stemcells frombonemarrow,ParketalandZamzametalhavesuccessfullytreatedvoids(gaps)insimplebonecysts[17,18].

STEM CELLS TO TREAT CARTILAGE DEFECTS WITH SCAFFOLDS:

Marcacci et al, used autologous MSCs used incombination with hydroxyapatite scaffolds for fillingof cartilage defects and reported good integrationof the grafts[19]. Cartilage once damaged has a verypoor ability ro repair itself; so application of newchondrocytes at the damaged site may give riseto formation of new hyaline cartilage. Autologouschondrocyte transplantation has been used by Jagercl al, to treat cartilage andbonedefects[20]. Abrasionchondroplasty, inwhichdrillholesaremade into thebone, showed good results with processed cells incombination with biodegradable gels.Wakitani et alusedMSCsharvestedfromiliaccrestinvitroandthenculturedinthelabfor1monthandthentransplantedthem to the site of cartilage defect using collagengel and covered the defect with a periosteal flap[21].SimilarlyBudaetal,reportedtheuseofMSCsforthetreatmentofosteochondral lesionsof the femurandtalus[22].

All above findings make it very clear that stemcells have the potential to treat several orthopedicconditionsduetotheirabilitytogetdifferentiatedintoosteocytes,chondrocytesandmusclecells.OurstudyfurthershowshowpatientsgotrecoveredfromAVNbyusingautologouschondrocytetransplantation.

MATERIALS AND METHODS:

Here we present some of the case studiesperformed in the laboratory where application ofstem cells in the patients of AVN of femoral headwereperformed.Aprospectiverandomizedtrialon15patientsofdifferentagegroupsundergoingtreatmentforAVNoffemoralheadwasconducted(Table1).Allof themunderwent stemcell therapybywhich stemcellsfromtheirbonemarrowandadiposetissuewereisolated inthe laboratory;and later,afterprocessing,wereinjectedbackinthebody.Aftertakingthefollow-upswefoundthesepatientswererecoveringandthesuccessratioofrecoverydependsonvariousfactors.


AVNinbasicallygradedat4stagesaspertheFicatStaging

Stage 0X-ray:normalMRI:normalclinicalsymptoms:nil

• Stage IX-ray:normalorminorosteopaeniaMRI:oedemabonescan:increaseduptakeclinicalsymptoms:paintypicallyinthegroin

• Stage llX-ray: mixed osteopenia &/or sclerosis &/orsubchondral cysts, without any subchondrallucency(crescentsign-seebelow)MRI:geographicdefectbonescan:increaseduptakeclinicalsymptoms:painandstiffness

• Stage III X-ray:crescentsign&eventualcorticalcollapse

MRl:sameasXray

clinicalsymptoms:painandstiffness+/-radiationtokneeandlimp

• Stage IVX-ray: end stage with evidence of secondarydegenerativechange

MRI:sameasXray

clinicalsymptoms:painandlimp

Table 1: No. of patients treated for AVN of Femur head with Autologous Cell Therapy.

Subjects Sex Age BMI Stage Treatment1 M 27 24.3 1

AutologousCell

Therapy

2 M 26 26.9 13 M 45 31 34 M 26 23 25 M 46 28.3 46 M 27 25 17 F 32 26 1

AutologousCell

Therapy

8 F 47 28.3 39 F 34 22 210 F 26 25 211 F 38 27.1 212 F 27 22 I13 F 33 26 314 F 55 30.2 415 F 54 29.3 4

METHODOLOGY:

For all 15 patients case historywas taken and allwereeligibleforundergoingthistreatmentasperthestandard eligibility criterion confirmed after clinicaldiagnosis.Consentsweretakenfromallthe15patientsat the time of their autologous stem cell therapy.Followlngprocedurewasperformedforeverypatient.

100 cc of bonemarrowwas taken from the iliacboneof thepatientwith thehelpofabonemarrowharvesterinthemedicalfacilityandsamplewassenttothelaboratoryinanasepticsterilecondition.Similarly100ccperipheralbloodwascollectedfromthesamepatient’s body and was sent to the laboratory in anasepticsterilecondition.Allsampleswereprocessedbydensitycentrifugationmethodtoisolatemesenchymalstem cells from bone marrow and adipose tissue inseparate batches[23]. The isolated cells from bonemarrow were tested for cell count and cell viabilityafterwhichcellswerecharacterizedforMSCmarkersCD73, CD90, CD105[24].Molecular characterization oftheprocessedcellsconfirmedtheir identityasMSCs.Similarly isolated MSCs from adipose tissue weretested for cell count and cell viability andmolecularcharacterization with CD13, CD29 confirmed theiridentity[24]. Collectedperipheral bloodwasprocessedand platelet rich plasma [PRP] was prepared. Bonemarrow & adipose tissue derived stem cells withstromal factor were transplanted autologously alongwithPRP.After3months,reportsshowed impressiveresultsinallthesecases.Followupwastakenforayearafter every 3 months for individual patient. Patientsshowed good improvement symptomatically withfollowingindications.

1. Clinical findings showed that knee pain, hippain reducedandmobility andflexibilityor jointincreasedthanbefore.

2. Radiologicalfindings:Restorationofjointspacetonearnormalcy,articularsurfacewaswelldefined,sub-articulorgeodesweredisappearedwithsignsofnewcartilageformation.(Figure 1)


Figure 1. X-ray of a patient showing improvement in terms of bone growth difference after treatment.

X-Ray Fums Showing Bone Growth Difference

Role of Niche in stem cells differentiation and proliferation

X-raytakenafter3monthsfollowupofthepatientshowedsignsofnewcartilageformationwhichindicatesthe process of chondrogenesis. Studies have shownthat the microenvironmeet - also known as ‘niche’comprised of ECM (extracellular matrix), regulators,chemokines and cytokines play an important role inchondrogenicdifferentiation.TGFBs,IGFsandFGFshavebeenimplicatedinchondrogenesis[24].Besidesthecell-cellsignaling,cell-matrixinteractionscanalsoaltercellbehaviorandthusinfluencethecommitmentofMSCsinto chondrocyte Iineage[25,26].Alongwith theabove-discussedapplicationsofstemcellsatourlaboratory,someotherconditionsarealsobeinginvestigatedfortheir suitability for stem cell applications includingankylosing spondylitis, bone fractures, non healingfractures, osteoarthritis, sports injuries. Thoughapplication of stem cells iswell proven in orhopedicconditions,thetherapyalsolookspromisingforotherneurological andmetabolic disorders and clinical forwhichclinicaltrialsarebeingperformedworldwide[27].

SUMMARY:

Stem cell therapy based on the principle of theregenerativemedicine is an attractive option for thetreatment of intractable diseases. However, the useof stem cell therapy in all the conditions discussedaboveissubjectofindividualtreatment.Manyofthesestudieshaveshownquickgoodresultsbutatthesametimefewcaseshaveshownslowimprovement intheconditions.Asdiscussedearlier,thismightalsobelinkedtotheselectionofthepatient,thetypeofcellsused,concentrationanddoseofthecellsused,applicationofcells,durationoffollowupandevaluationtoolsamongothers.Manymorelongtermprospectiverandomizedhumantrialsneedtohavegoodresultsbeforeonemayactuallyrecommendtheuseofthesecells.Itiscertainthatthefutureisgoingtobeexcitingwiththeuseofstemcells.Aparadigmshiftfromconventionalmodeoftreatmentstothenovelstemcelltherapyistheneedofthemodernhealthcare.Highqualityresearchcoupledwithpracticalapplicationsinthecellularmedicinehasset a stage for successful tissue engineering in vitro.Stem cell therapy has brought in a lot of optimistichopeamongstresearchers,doctorsandbutobviouslythepatients.Atthesametime,establishingthesafetyprofile of these therapies is equally important toavoid complicationsas there is a strongdemarcationbetweenhypeandhoperegardingthepotentialuseofthesetherapies.

REFERENCES:

1. KaiserLR.Thefutureofmultihospilalsystems.TopHealthCareFinance1992.Summer;18(4):32-45.

2. Anderson DJ. Gage FH, Weissman IL. Can stemcellscrosscelllineageboundaries?NatMed.2001Apr:7(4):393-5.

3. Ehnert S, Glanemann M, Schmitt A, Vogt S,ShannyN,NusslerNC. The possible use of stemcells inregenerativemedicine:dreamorreality?.LangenbecksArchSurg2009Nov:394(6):985-97.

4. TakahashiK,YamanakaS.Inductionofpluripotentstem cells from mouse embryonic and adultfibroblast cultures by defined factors. Cell 2006Aug;126(4):663-76.

5. Rodolfa K. Di Giergio FP. Sullivan S. Definedreprogramming: a vehicle for changing thediffarentiated state. Differentiation 2007 Sep;75(7):577-9.

6. Mafi R. Hindocha S, Mafi P, Griffin M, KhanWS. Sources of adult mesenchymal stem cellsapplicable for musculoskeletal applications-asystematicreviewof the literature.OpenOrthopJ2011(5Suppl2):242-8.

7. Ohgushi H, Caplan AI, Stem cell technology and


bioceramics: from cell to gene engineering. JBiomedMaterRes1999:48(6);913-27.

8. Kotobuki N. Hirosc M, Takakura Y, Ohgushi H,Cultured autologous human cells for hard tissueregeneration:preparationandcharacterizationofmesenchymalstemcellsfrombonemarrow.ArtifOrgans2004Jan;28(1);33-9

9. Proekop,D.J.(1997).Marrowstromalcellsasstemcells for non-hematopoietic tissue. Science276,71-74

10. HernlgouP,MathieuG,PoignardA,ManicomO,Beaujean F, Rouard H. Percutaneous autologousbone-marrow grafting for nonunions. Surgicaltechnique. J Bone Joint Surg Am 2006 Sep; 88Suppl1(Pt2)322-7.

11. Hernigou P, Poignard A, Beaujean F, Rouard H.Percutaneous autologous bone marrow graftingfor nonunions. Influence of the number andconcentrationofprogenitorcells.JBoneJointSurgAm.2005Jul;87(7):1430-7.

12. BurwellRG.The functionofbonemarrow in theincorporation of a bone graft. Clin Orthop RelarRes.1985Nov;200:125-41.

13. Fernandez-BancesI.Perez-BasterrecheaM,Perez-Lopez S, Nuilez Batalla D, Fernandez RodriguezMA, Alvarez ViejoM et al., Repair of long-bonepseudoarthrosis with autologous bone marrowmononuclearcellscombinedwithallogenicbonegraft.Cytotherapy.2013May;15(5):571-7.

14. Sen RK. Management of avascular necrosis offemoral head at pre-collapse stage. Indian JOrthop.2009Jan;43(1):6-16.

15. WangT,WangW,YinZS.Treatmentofosteonecrosisofthefemoralheadwiththoroughdebridement,bone grafting and bone-marrow mononuclearcells implantation. Eur J Orthop Surg Traumatol,2013Jan.

16. Sen RK, Tripathi SK, Aggarwal S, Marwaha N,Sharma RR, Khandelwal N. Early results of coredecompression and autologous bone marrowmononuclear cells instillation in femoral headosteonecrosis: a randomized control study. JArthroplasty,2012May;27(5):679-86.

17. ParkIH,MicicID,JeanIH.Astudyof23unicameralbonecystsofthecalcaneus:openchipallogeneicbonegraftversuspercutaneousinjectionofbonepowder with autogenous bone marrow. FootAnklelnt.2008Feb;29(2);164-70.

18. ZamzamMM,AbakAA,BakarmanKA.Al-JassirFF,KhoshhalKJ,ZamzamiMM.Efficacyoraspiration

and autogenous bone marrow injection in thetreatmentofsimplebonecysts.IntOrthop,2009Oct;33(5):1353-8.

19. MarcacciM,KonE,MoukhachevV,LavroukovA,KutepovS,QuartoR,etal.Stemcellsassociatedwith macroporous bioceramics for long bonerepair:6to7yearoutcomeofapilotclinicalstudy.TissueEng.2007May;13(5):947-55.

20. Jiger M. Jelinek EM, Wess KM, ScharfstadtA, Jacobson M, Kevy SV. et al. Bone marrowconcentrate: a novel strategy for bone defecttreatment. Curr Stem Cell Res Ther, 2009 Jan;4(1):34-43.

21. WakitaniS,NawataM,TenshoK,OkabeT,MachidaH,OhgushiH,Repairofarticularcartilagedefectsin thepatellofemoral jointwithautologousbonemarrowmesenchymal cell transplantation: threecase reports involvingninedefects infiveknees.JTissueEngRegenMed.2007Jan-Feb;1(1):74-9.

22. BudaR,VanniniF,CavalloM,GrigoloB,CenacehiA,GianniniS.Osteochondral lesionsoftheknee:a new one-step repair technique with bone-marrow-derivedcells.JBoneJointSurgAm.2010Dec.;92Suppl2:2-11.

23. ThanRS,BolandG,TuliR.Adultmesenchymalstemcells and cell-based tissue engineering. ArthritisResTher2003:5:32-45..

24. Mitchell JB, Mclntosh K. Zvonic S et al.Immunephenotype of human adipose-derivedcells:temporalchangesinstromal-asseciatedandstemcell-associatedmarkers.StemCells2006;24:376-85.

25. DominiciM.LeBlancK.Muellcr I,etal.Minimalcriteria for defining mulrlporent mesenchymalstromalcells,TheInternationalSocietyforCellularTherapy position statement. Cytotherapy 2006;8:315-317.

26. Goessler UR, Bugert P, Bieback K, et al. In-vitroanalysisoftheexpressionofTGFbeta-superfamily-members during chondrogenic differentiation ofmesenchymalstemcellsandchondrocyresduringdedifferentiationincellculture.CellMolBioILett2005;10;345-362.

27. TripathySK,BeheraP,SenRK,GoyalT.Applicationof stem cells in orthopaedlc conditions: what isthecurrentevidence?OAOrthopaedics2013May01;1(1):3


Changing Paradigms in Healthcare Medicine

Pradeep v. Mahajan1*, Anurag P. Bandre1, Nitin S. Desai1

1.ChairmanandManagingDirector,StemRxBioscienceSolutionsPvtLtd.,R-831,T.T.C.,

ThaneBelapurRoad,Rabale,NaviMumbai,Maharashtra,India

*CorrespondingAuthorandAddress:Dr.PradeepV.Mahajan,

StemRxBioscienceSolutionsPvt.Ltd.,R-831,T.T.C.,ThaneBelapurRoad,

Rabale,NaviMumbai,Mahatarashtra,India.Email:[email protected]

ABSTRACT:

Thescienceofhealthcaremedicineischangingrapidlyandcomingoutofitsshellwithbetterprospects.Thehealthcaresectorisnownotjustlimitedtotheoldconceptofonepathogencausingonediseaseandtreatedbyonemedicine;butitisbeingreplacedbytheapplicationofnewertreatmentmodalitiestotreatdiseasesanddisorders.Theconceptofdonororgantransplantisnowchangedtoconceptoforganregeneration(usingIPSCs-inducedpluripotentstemcellsorevenusingautologousstemcells).RegenerativeMedicinehasplayedabigroleinthisparadigmshift.TheRegenerativemedicine-abranchoftranslationalresearchusesstemcellsintissueengineeringandmolecularbiologywhichdealswiththeprocessofreengineeringorregeneratinghumancells,tissuesororgansatthedefectivesitestorestoreorestablishnormalfunction.TheapplicationsofRegenerativeMedicineareworldwideandit isnowimportanttoenhancetheefficacyoftheseappicationsbymergingthedistinguishingfieldofscienceusingthevariablesthosecanchangetheparadigmsofregenerativemedicine.

Keywords: Regenerativemedicine,stemcells,IPSCs,organregeneration

INTRODUCTION:

Stemcellsarenotnewtousandweallknowthe importance of therapeutic applications of thestemcells indifferentdiseases anddisordersbutwearealsoawareof the fact that stemcell therapyhassparkedmuchcontroversyoverthelastseveralyears;asthisfieldisstillsurroundedbyethical,legal,politicalandsocialbarriers.Safetyandefficacyissuesinuseofstemcellshaveraisedtheconcernabouttheiruse inthetreatmentofdifferentdiseasesanddisorders.Butif these issues are properly taken care of, stem cellscanplaytheroleofwonderdruginmodernmedicine.Mostofthemedicalexpertsareawareofthefactthatold and conventionalmedical therapies have proventobeineffectiveanduselessformanyofthedreadfuldiseases. In such cases, where people are asked tocompromise with their health condition, stem cellscan really prove a medicinal boon to such patients.Theregenerativemedicinemarkethasalreadystartedencroaching European and US countries with stemcell products, therapies and technologies. There is

no doubt that the upcoming era will be of cellularmedicinewithmoreandmoretreatmentmodalities.AsshowninFig.1,itisclearhowfastthisparallelscienceof regenerative medicine is showing its potential inthe global healthcare market. What requires nowis to understand itswide scope and to focus on theusefulnessofthisscienceinthemass.

Regenerativemedicinebasedontheapplicationsof stem cells comprises a market for regenerativeproductsandcanbeseengrowingexponentiallyinthecomingyears.Stemcellshavewideuseinthetreatmentsoforthopedicconditions,neurodegenerativeconditions,cardiovascular diseases and even several chronicmetabolic disorders. Other disorders that will benefitfrom cell therapies include diabetes, inflammatorydiseasesandagingdisorders.Thesuccessratiosmayvarywithrespecttodiseaseconditionandthetypeoftherapyused.Manyatimesitisseenthatefficacyoftreatmentisdependentonthealliedtreatmentmodalitiescoupledwiththemainstemcelltherapy.


Fig 1. (Source: Report #S520, “Tissue Engineering, Cell Therapy and Transplantation: Products, Technologies & Market Opportunities, Worldwide, 2009-2018.”)

These variables may play an important role indecidingthefateofstemcelltherapyincontrollingthesignsandsymptomsofthedisorders.

THE VARIABLES OF CHANGING PARADIGMS FOR REGENERATIVE MEDICINE:

The distinguishing fields of allied treatmentmodalitieswhich can really revamp the regenerativemedicine comprise of game changing technologieslike roboticmedicine, telemedicine, digitalmedicine,genomic&molecularmedicineandnanomedicine.

STEM CELLS AND ROBOTIC MEDICINE:

Stemcellsaretherepairingkitswhichwecarryinour body. There aremany sources of stem cells likecordblood,cordtissue,bonemarrow,adiposetissuewhich can be used for therapeutic applications. Inautologouscellulartreatmentpatientsownbodycellsare transplantedback afterprocessing them in vitro.Robotic medicine is not new to health care. We allare aware of the Vinci Surgical System that arose in2000.Roboticsystemhaseasedthecomplexsurgeriesand isbasedonhighendmechanics. In regenerativemedicine, stem cell harvesting procedures andtransplantprocedures candefinitelybe coupledwiththeuseofroboticarms;andsetthenewperfections.Recently in 2014 Bollinger M, Wechsler L and SteinJ, in their studies have concluded that robotics,stem cells and brain computer interfaces all havetremendouspotentialtoreducedisabilityandleadto

betteroutcomesforpatientswithstroke[1].Howevercontinued research and funds will be required tostrengthenthesefieldsasmergingcapacitiesofthesesciencesarestillinanutshell.

STEM CELLS AND TELEMEDICINE OR DIGITAL MEDICINE:

The wireless innovations in healthcare haverevolutionized the concept of remote consultations.Using high end technologies and advanced ways ofcommunication,nowit’spossibletotransferthemedicalinformationthroughaudiovisualmedia.WiththeuseofGooglemirror,holographicconsultationsarepossibleindoors, sitting at home, virtual medical visits andholographicconsultationshavemadecommunicationeasy;andwillbethemilestoneforcreatingawarenessabout the importance of regenerative medicine inmass. The cost effective and time saving parametersfurther add to the importance of this area. Digitalmedicineisamultidisciplinarysubjectthatarosewiththemergingofmedicineandnewdigitaltechnologies;and covers subjects such as medicine, mathematics,informatics,electronicsandmechanicalengineering.Itcanbeusedforbasicresearch,clinicalstudiesandforthetreatmentofvariousdiseases[2].ZhuWeifunetalin2014hasshowntheimportanceoftelemedicineanddigital management in repair and regeneration afternerveinjuriesandothernervoussystemdiseases[3].

STEM CELLS AND NANOMEDICINE:


Nanotechnologyallowsscientiststocreate,exploreandmanipulatenonmaterialmeasuredinnanometerswhichcanbeusedinadvancedsurgeries.Theclinicalpotential of targeted nanomedicine delivering tocancerstem-likecellsisnowworldknownasSang-SecKimetalhaveshowntheImportanceofnanomedicinetreatmentsoncancerpatientsforthedeliveryofstemcells.Theydevelopedatumor-targetingnanodeliveryplatform(scL)forsystemicadministrationofmolecularmedicines. In various animalmodels, post treatmentwith the scl, nanocomplex carrying variouspayloads,they observed exquisite tumor-targeting specificityand significant antitumor response with long-termsurvivalbenefit[4].

STEM CELLS AND BIOENGINEERING:

Regenerative medicine also includes use ofbiodegradable scaffolds with stem cells and theirsafe implantation at the defective sites. Combiningstem cells with biomaterial scaffolds provides apromisingstrategyforengineeringtissuesandcellulardelivery. Biomaterials can be natural or synthetic,proteinbasedorpolysaccharidebased.Proteinbasednatural biomaterials are collagen, silk and fibrinwhile polysaccharide based natural biomatertals areagarose, alginate, hyaluronan and chitosan. Syntheticbiomaterials include PLGA (poly lactic-co-glycolicacid) andPEG (polyethyleneglycol). The typeof thebiomaterial or the cues used, play an important roleindecidingthefateofthestemcellsimplanted.Stemcellsalongwiththesebiomaterialshavebeenusedinmany treatmentmodalities fororthopedic conditionslikecartilagerepair,bonefractures,tendoninjuriesandmanymore.Besidesorthopedicconditions,stemcellswithscaffoldshaveproventheirefficiencyincosmeticsurgeries and even cardiac operations. Cell sheets ofMSCs(mesenchymalstemcells)haveshowntoimprovecardiacfunctionwhenusedwithcollagen[5].

ORGAN DEVELOPMENT WITH 3D PRINTING TECHNOLOGY:

Tissue engineering technology promises to solvethe organ transplantation crisis. The assembly ofvascularized 3D soft organs remains a big challenge.Organ printing defined as computer aided, jet based3Dtissue-engineeringof livinghumanorgansoffersapossiblesolution.Organprintinginvolvesdevelopment

of blueprints for organs followed by actual organprinting and organ conditioning. Cell printers thatcan print gels, single cells and cell aggregates havebeendeveloped. Solidified thin layersof sequentiallyplaced,thermo-reversiblegelservesasprintingpaper.Combinationofengineeringapproachwithembryonictissue fluidity concept of developmental biologyenables the creation of a new rapid prototyping 3Dorganprintingtechnology,whichhasthepotentialtoaccelerateandoptimizethetissueandorganassemblydramatically [6].3Dprintingtechnologiesarealreadybeingusedinpharmaceuticalresearchandfabrication,and look promising in bringing transformation.Advantagesof3Dprintingincludehighreproducibility,precisecontrolofdropletsizeanddoseandtheabilityto produce dosage formswith complex drug-releaseprofiles.

Complexdrugmanufacturingprocessescanalsobestandardized through theuseof3Dprinting tomakethemsimplerandmoreviable.3Dprintingtechnologycould also prove beneficial in the development ofpersonalizedmedicine[7].

REVAMPING OF HEALTHCARE SECTOR:

Regenerativemedicinecoupledwithall theabovementionedadvancementsandcan revamp theentirehealthcaresector.Duringthishappeningtheparadigmof healthcare has shifted towards cellular medicinefromtheoldconventionalmedicine.Intheduecourseof time surgeons have done number of successfultransplantswiththehelpofstemcells.Foraninstance,hip replacement is taken over by hip regenerationand insteadof spendingmillionsofdollarson insulininjections,nowitispossibletoregenerateinsulinfactoriesinvivotoeliminatediabetescompletely[8].Similarlyinseveralorthopedicconditions,neurodegenerativeandneurodevelopmentalconditions,stemcelltreatmentshave proven their existence. In the coming yearsresearchers may introduce ‘stem cell gene therapy’for immunomodulatory treatments in autoimmunedisorders.GroundbreakinginventionofTcellseducatortherapyforautoimmunedisordersbyDr.YongZhao[9]ashighlightedbytheAmericanDiabetesAssociationat72nd Scientific Sessions (Philadelphia, 2012) is one ofthe8majorbreakthroughsandinitiativeswhichweredonein2012.Stemcellgrowthandmigrationonnano-


fibrous scaffoldsandmicro-fluidic channelson siliconchipwerestudiedusingneuralstemcellsisolatedfromadult rats. Possibly this technology of using neuralstemcellswillrevolutionizethetreatmentprotocolsinelectrical signal neural transmission system [10]. TheinventionofVSELs(Verysmallembryolikestemcells)orDCs(dendriticcells)havealreadyraisedthestandardsoftreatmentmodalitiesincancermedicine[11].

DISCUSSION:

Scienceissoevolvedthattheconceptofdevelopinga body organ which looked like dream once uponatime isnomorefiction;buthas turned into realitywith thehelpof3Dprintingandscanner technology.Now it ispossible todeveloporgans like liver,kidneyetc. This clearly indicates that regenerativemedicineis the future of medicine and conceptually the dayisnofarwhenonecanaccesstheorganshopseasilyin healthcare market. However this field is undersiegepoliticallyandfinancially, so itneedsanurgentattention to promote this science which has truepowersofrevampingthecompletehealthcaresector.Medicaltechnologyisgrowingrapidly.Severaldiseasescannowbetreatedveryeffectivelywiththeapplicationof implantable devices that restore physical andmechanicalfunction,suchasreplacementofhipjointsor restoration of heart rhythms by pacemakers. Thetechniques,however,areratherlimited;andbiologicalfunctioncannotbe restored through theuseof inertmaterialsanddevices.Patientstodaydemandqualityhealth care and health care practitioners demandstability which has to be taken care of; otherwise itwill lead to the problem of health crisis. This mayleadtolegislationexpandingthescopeofpracticeforallied health care providers, thereby circumventingphysicians and undermining our control. If we reallywant to avoid the health crisis problem, revampingof healthcare medicine is necessary and globally itrequiresanurgentattentiontosteptowardsabetterhealthcaresystem.

REFERENCES:

1. Bollinger ML, Wechsler LR, Stein J. Robotics,stem cells, and brain-computer interfaces inrehabilitation and recovery from stroke: updatesandadvances.Am JPhysMedRehabiI.2014;93(11Suppl3):S145-54.

2. Wang LS, Luo YR. Digital medicine and digitalorthopedics: a hot topic in tissue engineering.Zhongguo Zuzhi Congcheng Yanjiu Vu LichuangKangfu,2008;12:6374-6380.

3. ZhuW,ZhaiY,SunD,andZhaoJ.Telemedicineanddigital management in repair and regenerationafternerveinjuryandinnervoussystemdiseases.NeuralRegenRes.2014;9(16);1567-1568.

4. KimS,RaitA,RubabF,RaoAK,KiritsyMC,PirolloKF,WangS,WeinerLMandChangEH.Theclinicalpotentialoftargetednanomedicine:Deliveringtocancer stem-like cells. Molecular Therapy 2014;22(2):278-291.

5. Miyahara Y, Nagaya N, Kataoka M, Yanagawa B,Tanaka K, Hao I-L Ishino K, Ishida H, Shimizu T,Kangawa K, Sano S, Okano T, Kitamura S, MoriH. Monolayered mesenchymal stem cells repairscarred myccardium after myocardial infarction,NatMed200612:459-465.

6. MurphySVandAtalaA.3Dbioprintingoftissuesandorgans.NatureBiotechnology-2014;32,773-785,

7. UrsanI,ChiuL,PierceA.Three-dimensionaldrugprinting:astructuredreview. JAmPharmAssoc.2013;53(2):136-144

8. Pagliuca FW, Millman JR, Gurtler M, Segel M,Dervort AV, Ryu JH, Peterson QP, Greiner D andMeltonDA.GenerationofFunctionalHumanPan-creaticβCellsInVitro.Cell.2014;159(2):428-39

9. Yong Zhao, Stem Cell Educator Therapy andInduction of Immune Balance. Curr Diab Rep.2012;12(5):517-23.

10. Geng Z, Du J, Zhang L, Yang C, Wang W andLi Z (2010). Separation And Enrichment OfMesenchymal Stem Cells On A Chip, In 14thInternationalConferenceonMiniaturizedSystemsfor Chemistry and Life Sciences; Groningen, TheNetherlands

11. NagarajS,ZiskeCandSchmidtIGH.Dendriticcell,the immunotherapeutic cell for cancer. Indian J

MedRes2004;119,133-138


Success stories those created history

INAYA CHAVAN (CEREBRAL PALSY)CASE HISTORYBabyInayaChavanwasborninJanuary2015asanormalchildwithlowbirthweight.

Inthefirstweekafterthebirth,herwristsgotbentandherfeetstarted pointing downwards. At about 3 months of age, hereyeandneckmovementsstartedbecomingjerkyandrandom.

Whenthepareantsconsultedtheirfamilydoctor,basicmedicationsandnutrientsupplementswereprescribed.At6monthsofage,shesufferedfromanepilepticattack.Lateron,shestartedgettingseizuresanytimeduringtheday.Shecontinuedtohaveepilepticepisodessincethen.Inayacouldnotmoveorliftherlegs.STEMRX TOUCHFor Dr. Mahajan this was an extremely challenging case as the baby’s age was very less.Investigationwasdonetounderstandherconditionforthetreatment.3sessionsofcelltherapyweresuggestedforheroveraperiodof21days.Fortunately,Inayastartedrespondingquickly.After three sessions, she exhibited tremendous improvement in her condition and startedrespondingtovoicecommandswithimprovementinhereyemovements.TESTIMONIAL (Mrs. Namrata Chavan)

“WevisitedmanyhospitalslikeHinduja,KEM,JJetc.andweweretoldthatourbabyisabnormal.Ihadbecomenervoustohearthis.ButGod’sgrace,wegotachancetomeetDr.Mahajan,herelievedusbystatingthatourbabyisnotabnormalandassuredustotreather.Aftertreatment,sheshoweddrasticchanges.”

SUSHANT CHAVAN (MULTIPLE SCLEROSIS)CASE HISTORY

AnengineerfromSangli,SushantChavanwassufferingfrombodyacheforfiveyears.Duringhiseducation,hishealthwasdeterioratingslowlyandfinallyhegotcompletelybedridden.Afteramedicaltest, inOctober2011hewasdiagnosedwithmultiplesclerosiswhichshatteredhisfamily.STEMRX TOUCHWhilegoingthroughthistoughsituation,hisfamilyheardaboutStemRxandtheydecidedtovisitheretoconsultDr.Mahajan.Doctor,afterevaluatingSushant’sphysicalcondition,startedthe treatment immdiately.Within 2monthsof thefirst stageof treatment, his body startedrespondingwell.Nowhecanwriteandspeak.Healsocanwalkbytakingsupport.TESTIMONIAL“Iwasnotabletomoveatall.Ihadtodependuponothersevenforcarryingoutdailyactivities.Ihadstartedlosingmycourageandevenmyhope.ButIcameacrossanarticlebyDr.Pradeep


Mahajanandmyfamilycontactedhim.NowIamfeelingbetterandmyhealthisgettingimprovedfast.NowIamextremelyhappybeingabletostartmystudiesagain.”

HEDAYATULLAH (ANKYLOSING SPONDYLITIS) (https://www.youtube.com/watch?v=ks4wN0d9bIo&feature=youtu.be)CASE HISTORY

Hedayatullah from Afghanistan was suffering from Ankylosing Spondylitis since 12 years. He washavingpainthroughouthisbodyfromnecktolowerbackandallthejoints.HecametoknowaboutStemRxandDr.Mahajanthroughinternet.Dr.MahajanassuredhimtotreathisailmentandaskedhimtocometoIndiaforthetreatmentassoonaspossible.STEMRX TOUCH

WhenhevisitedStemRx,thetreatmentplanwasdecided.Afterthetreatmentstarted,hisbackpaingot90%cured.Evenhisdependencyonpainkillerscametostop.TESTIMONIAL“Iamabout90%ok.Iwashavingabout20painkillerseverydayforbackacheaswellasjointpain.NowIhavestoppedtakingpainkillersandstillthereisnopain.IamextremelythankfultoDr.Mahajan.”

JAGANNATH BHAVARE (https://www.youtube.com/watch?v=mBgOnWd5UUk&-feature=youtu.be)CASE HISTORY

JagannathBhavare’sailmentbeganwithsuddenpaininlowerback.Allthedoctorsconsultedinsisteduponoperationwhichforcedhimtogetthatdone.However,afteroperation,hestartedsufferingfromstoppageofurination.Whiletreatingthis,hegotinfection.Thiswasdiagnosedtobeduetodamagetothenervehappenedduringthepreviousoperation.Theseriesofhealthproblemsoccuredthiswaycompelledhimtosearchforadoctorwhowouldassurecompletecure,whenhereadaboutStemRxinnewspaper.STEMRX TOUCHAfterevaluationandstartoftreatment,withinashockinglyshortspanof2dayshisurineflowgotnormalised.Hisdependencyoncathetercametoend.TESTIMONIAL“Ihadtousecatheterandplasticbagswhilepassingurine.Afterstemcelltherapy,theurineflowwascompletelynormalized.”

ARUN LAKHANI (BILATERAL AVN) (https://www.youtube.com/watch?v=k-s4wN0d9bIo&feature=youtu.be)CASE HISTORYArunwassufferingfrombilateralAVN.InhislefthipjointhewassufferingfromthirddegreeAVNandrighthipjointformseconddegreeAVN.Orthopedicsurgeonshadsuggestedhimtotalhipreplacementsurgery. But he was reluctant to do that considering his younger age. He learnt about stem celltreatmentandDr.PradeepMahajanthroughinternet.


STEMRX TOUCH

Aftertreatmentthepaingotcompletelycuredandthepersonisabletowalkproperly.TESTIMONIAL

“Afterthetreatment,Iamhappyandmypainisgone.ThankyousomuchDr.PradeepMahajan.”

MOHAMMAD SHAHID (ANKYLOSING SPONDYLITIS) (https://drive.google.com/file/d/0B7_h4U343DRCNWJTUVhxaGg4R0k/view)CASE HISTORY

MohammadShahidwas suffering fromAnkylosingSpondylitis.Hewashavingunbearablepainanddifficultyinmovinghisneck.STEMRX TOUCH

Withstemcelltherapyhegotrelieffrompain.Nowheisabletorotatetheneckfreely.TESTIMONIAL“Ihavebeentakingtreatmentfromsomanyplaces,butthistherapyworkedwellforme.Thepainisgoneandmovementisimproved.”

SAJJAD (TYPE 1 DIABETES) (https://drive.google.com/file/d/0B7_h4U343DRCNFF-pZ3JTODctOHc/view)CASE HISTORY

Sajjad,amedicalstudentfromIraqwassufferingfromtype1diabetessince15years.Hehadtotakeinsulin,stillhisdiabeteswasnotcontrolled.Thebloodsugarlevelwas250-300.HecametoknowaboutStemRxandDr.Mahajanwhilesearchingonnet.STEMRX TOUCH

StemRxsuggestedhimsomelifestylemodificationsandphysiotherapyalongwiththeregulartreatment.After15daystherewasimprovementintheoverallconditionofthepatient.TESTIMONIAL

“Iamveryhappytoseetheimprovement.PreviouslyIhadsomuchweaknessbutnowIfeelbetter.”

TRISHA KULKARNI (LICHEN PLANUS) (https://drive.google.com/file/d/0B7_h4U343DRCUnZzc01xeFF2ZUk/view)CASE HISTORYTrishawassufferingfromlichenplanus(skinrashwhichitchesalotandthenconvertstoblackspots)sincetheageof10years.Shetriedallsortsofmedicines:alopathy,ayurvedicaswellashomeopathic.ShecametoknowaboutStemRxthroughnet.STEMRX TOUCH

After3treatmentsessionsshesawmajorchangesintheappearanceofherskin.Theitchingwasgoneandskinstartedbecomingnormal.TESTIMONIAL

“IamveryhappyforthetreatmentandI’msureDr.Mahajanwillgetmecuredcompletely.”


DR. ADITI THORAT (MENORRHAGIA) (https://mail.google.com/mail/u/0/#inbox/1572d7035bc71239?projector=1)

CASE HISTORY

AditiwassufferingfrommenorrhagiainducedbyPCOD(polycysticovarysyndrome).Shewasalsotakingtreatmentforhypothyroidism.Shewasshowingmanysymptomsincludinghypertension,palpitationsandbreathlessness.Menorrhagiahadledtodroppedhaemoglobinlevelandalotofemotionalstress.Withmedication and pills, her haemoglobin levels got normalised, still the underlying problem ofmenorrhagiacouldnotbecuredcompletely.STEMRX TOUCH

Within a period of 10 days, that is from 10th November to 20th November, her periods aswell asemotionalstate,bothgotimproved.ShebeatbreathlessnessTESTIMONIAL“IfeelenergeticthewayIusedtobewhenIusedtobeincollege.Iamhavingmoreandmorepositivethoughts.Iamtryingtoovercomethingsandit’scomingonitsown.Thetherapyisamazing!”

PATRICK (EMPTY NOSE SYNDROME) (https://www.youtube.com/watch?v=mB-gOnWd5UUk&feature=youtu.be)CASE HISTORY

PatrickfromAustraliawassufferingfromemptynosesyndromesince6years.Theendoscopicevaluationshowedtheinferiorturbinateonleftcompletelyeroded.STEMRX TOUCHDr.Mahajan prepared a totally customized protocol by using self limiting scafolds, autologus cellsand growth factors. After aweek endoscopy showed improved vasculature. Patient experienced aremarkabledifferenceinbreathingsensationwithfirstweekoftreatmentitself.TESTIMONIAL

“Foralmost6years, Iwasfeelingdepressiveduetoemptynosesyndrome.Wehadapproachedlotmanydoctorsinlast6years.ItwasagreatdecisiontocometoIndiafortreatment.Dr.Mahajanandhisteamcooperatedverywellandmademytreatmentpossible.”


Case study : Neurogenic BladderIntroduction:

Lumbarspinalstenosisisacondition,commonamongelderlypersons,whichcausesintractablelegandbackpain.Decompressivelaminectomyistheprocedureadvisedthatcreatesspaceinthespinalcanaltorelievepressureinthespinalcord.However,theprocedureisassociatedwithahighincidenceofneurogenicdysfunctionofthedetrusormuscle(hypoorhypercontractility),whichisthemuscleassociatedwithvoidingofurine.Apartfromimpairedbladdercompliance,detrusordysfunctionofprolongeddurationmayleadtohydronephrosisandrenaldeterioration.Thepresentgoalsofthemanagementofneurogenicbladderarethepreservationoftherenalfunctionandincreasingthequalityoflifeforpatientsbyminimizingcomplications.However,itisnotpossibletoachievebladderfunctionrestorationandtissuerepairasthesetechniquesdonotresultinneuronalregeneration.Mesenchymalstemcells(MSCs)augmenthealingthroughcellreplacementandstimulationofcellproliferationandangiogenesis.Weherebypresentacaseofneurogenicbladdersuccessfullymanagedwithautologousmesenchymalstemcells.

Case Report:

A65-year-oldmalepatienthadcomplaintsofinabilitytomicturatesince3years,despitepresenceofsensationofbladderfullness.Hehaddiabetesmellitusandhypertensionsince14years.Pasthistoryrevealedthatthepatienthadcomplaintsofpainandnumbness/tinglingsensationinhislowerbackandlimbsbefore3-4years.Followinginvestigations,itwasrevealedthatthepatienthaddischerniationinhislumbarregionandlaminectomyprocedurewasrecommendedtohim.Thisprocedureaswellas long-standinguncontrolleddiabetesandneuropathy ledtogradualloss of bowel and bladder function. His ability to micturate voluntarily was lost completelywithin a year following laminectomy procedure and he would frequently get constipated.Sincethen, thepatientwasoncontinuousself-catheterizationtoaid in thepassageofurine.Hewasonmedicationtomanageconstipationthoughreliefwasnegligible.Cystometrydonepriortocellulartherapyrevealedreduceddetrusorcompliance.Voidingsequencealsoshowedabsenceofvoluntarydetrusorcontractionleadingtoseverevoidinginefficiencyandretention.Thechangesreflecteda lesionofthelowersacralnerverootswithanelementoffixeddistalsphincterobstruction.

Stem Cell Therapy

Cellulartherapywithautologousbonemarrowmesenchymalandadiposederivedstemcellswasrecommendedtothepatient.Approximately100mLofbonemarrowfromtherightiliaccrestand70–80mLofadiposetissuefromrightglutealregionwereaspiratedunderlocalanesthesia.Mesenchymalstemcellswereadministeredthroughintrathecaland intramural routes. Under USG guidance, bone marrow and adipose derivedmesenchymal stemcellswere injected in the transmural, submucosal and intramurallayersoftheurinarybladder.Thecellswereadministeredatdifferentlocations,namely,


fromthedometolateralwallandneartheneckofthebladder.

Results:

The patient was able to micturate voluntarily and catheter was removed on the 10th dayfollowing cellular therapy. In the followingweek, the patient regained someof his ability todefecatevoluntarily.Cystometry revealed increaseddetrusorcompliance, reducedsensationsand increased capacity. One month following cellular therapy, further improvement wasnoticed inbothmicturitionanddefecation.Thepatienthasdiscontinuedthemedications forconstipation.Pelvicfloorstrengtheningexerciseswereadvisedwhichthepatientcontinuestoperformregularly.

Discussion:

Under normal conditions, the detrusormuscle, bladder neck and striated external sphincterfunction as a synergistic unit for adequate storage and complete evacuation of urine. Thebladderandsphincterareinnervatedbythespinalconus,whichislocatedattheL1vertebra.Thedetrusormuscleisinnervatedbyfibersfrom2nd,3rd,and4thsacralroots;hence,anylesionintheregionorlumbarspinalsurgery(asseeninthispatient)mayleadtoneurogenicbladder.Inaddition,diabetesmellitusmayleadtoautonomicandperipheralneuropathyandimpairednerveconduction.

Stemcellshaveshownagoodpotentialforurothelial,neural,andsmoothmuscledifferentiationwhich are suggestiveof thepotential usesof cellular therapy inbladderdysfunction. Shuklaetal. (2008) reportedsuccessfuldifferentiationof stemcells intosmoothmuscle forbladderrepairandreplacement.Inthiscase,intramuralrouteofcelltransplantwasadoptedandpositiveresultsonbladderfunctionwerenoticed,whichconfirmsthemyogenicdifferentiationpotentialofmesenchymalstemcells.Similarly,thepotentialofmesenchymalstemcellsinspinalcordandothernerve related injuries hasbeendemonstrated.BonemarrowMSCswhen transplantedthrough the cerebrospinal (CSF) fluid have been shown to promote behavioral recovery andtissuerepairinspinalcordinjury.Huetal.showedthatintravenouslytransplantedbonemarrowstromalcellssurvivedintheL3-4andhadbeneficialeffectsontherecoveryofbladderfunctionintheratsafterspinalcordinjury.Inthepresentstudy,mesenchymalstemcellswereadministeredbyintrathecalroutethroughtheCSF,whichisamoretargetedwayoftransplantationofcellsforspinalcordinjurythanintravenousroute.Axonalregenerationhasbeenshowntobefacilitatedbyintrathecaladministrationofcells.Adiposederivedstemcells(ADSCs)administeredthroughintravenousor transurethral routeshaveshownsignificant improvement in increasingelastincontentinbladderandvoidingfunction.Also,studiesofbladderdysfunctiontreatedwithADSCshave shownhigh levels of smoothmuscle actinand smoothelin expression. These structuralproteins have been implicated in regeneration of muscle tissue. Although ADSCs have thecapabilitytodifferentiateintosmoothmusclecells,themainmechanismappearstobeparacrineactivitywhich reducesapoptosisandpreserves the ‘suburothelial capillarynetwork’.Chunetal.proposedatriplestemcelltherapyapproachusinghumanamnioticstemcells.Theystatedthat combined injection of three different lineages of early differentiating human amnioticfluid-derivedcells(myogenic,neurogenicandendothelial)restoresurethralsphincterfunction.


Despitethepositiveresultsintheabovementionedstudy,theinherentdisadvantageliesinthesourceofstemcells.Theadvantageofusingautologousstemcellsliesinitssafetyandeaseofharvesting.MSCscanbeisolatedandexpandedtogivetheneededtherapeuticdose.

The mechanism of therapeutic action of stem cells in neuronal injury is most probably acombinationoffunctions:reductionofapoptosisandhenceinflammatoryresponse,stimulationof endogenous neurogenesis, induction of angiogenesis and formation of new neuronalconnectionsinadditiontotheparacrineaction.

Conclusion:

Regenerative medicine and cellular therapy is a promising therapeutic approach for organdysfunctionandtissuereplacement.TheadministrationofBMSCandADSCthroughappropriateroutes in this case provided a mixed population of cells and growth factors which enabledus toharness themaximumpotentialof thecells.Nevertheless, regular follow-up tomonitorprogression/improvementoftheconditionismandatory.Also,furthertrialsandnovelroutesofadministrationarenecessarytoimproveefficacyofcellulartherapyinvariousconditions.

Competing Interests:

Theauthorsdeclarethatthereisnoconflictofinterestsregardingthepublicationofthispaper.


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