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Tendon Pathology & Regeneration 2019

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Tendon Pathology & Regeneration 2019 Tendinopathy, Tendon Healing & Tendon Regeneration Alayna E. Loiselle, PhD Associate Professor IND 464 Musculoskeletal Basic Science Course October 21, 2019 Outline • Review of homeostasis • Effects of Aging • Disruptions in homeostasis • Pathogenesis of tendinopathy/ tendinitis • Mechanisms of regeneration and healing !"#$%#&'()*%)+,-.-&,*"&#%.&,&/#('%*0&1%1/+,.(%# 23456(#&2788,9:&&234:;2788,9:&<=>? @"-.&A=2B@&C87D 0"1%" !"#$%(')*+',-./ !"#$%&$"'!"#$%(')*+',-./ ;7%&5115';"<8'#4=#<1%&>5?'?"$" 23%4&$5%4'!"#$%(')*+',-./ +6"4&74'5$'"1(8'!%7*9%:(',-./ Tendon Cell Proliferation During Growth Grinstein eLIFE 2019 Tendon Cell Proliferation During Growth Grinstein eLIFE 2019 !"##$%&'%(%)*+ !"#$%&'()*+)(,%-,./0()%,1%%/(234452367 8*")$%9(&,+*-:;%'.#(2<= >%/9*/(&/9(+"-#$%().*:-.%-(?'*+(:&,.%/,-()*'/(@23<A523BA C--%--+%/,(*?(,.--"%(,"'/*D%'('&,% !%#-&0*(&-3%*-4 ,("-"*-".(&./& 0.10&-%#-"(2 Tendon Homeostasis Young Aged • Matrix composition and organization is not dramatically different • Decreased proteoglycan content • Changes in cell morphology Functional Consequences of Aging? FCU FDL TT Fascicle Ackermanal.,et 2017. JOR Tendon is not mechanically sensitive to aging to sensitive mechanically not is Tendon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ollagenase Induced Tendinopathy Induces degenerative changes via collagen degradation LD= low dose HD= high dose collagenase Orfei C et al. (2016) PLOS ONE 11(8): e0161590. Mechanically Induced Tendinopathy Low level Moderate High level • Fatigue loaded under anaesthesia Unloaded loading loading loading • Uphill treadmill running • Downhill treadmill running Induces matrix and cellular changes Fatigue Loading Induces Apoptosis N Andarawis-Puri et al., 2014. JOR Neviaser A. 2012. J Shoulder Elbow Surg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ummary of Tendinopathy Remodeling Balance Physiological exercise increases: proliferation collagen production tenocytic gene expression (w/o chondro/ osteo/adipo) Overuse/ Fatigue: Matrix Damage Tenocyte apoptosis Effects of pathology and/ or co-morbidities: promote degeneration +/- inflammation Smoking obesity high cholesterol Future Directions • Continue to identify co-morbidities that predispose or accelerate tendinopathy • Most clinical data are from late stage pathology • Beginning to use genetic animals models to better understand tendinopathy !"#$%#&'"()*#+ ! ,-../...&0"#$%#&1"2(*1&21%3"$41"5&2"1&6"(1 ! 78"1&9:.&;*))*%#&*#&(55%3*(0"$&<"()0<&3(1"&3%505 ! '"()*#+&*5&3%=2)*3(0"$&>6&53(1&?%1=(0*%# @%1=()&0"#$%# A3(1&!*554" B$<"5*%# !"#$%# C"$53(2"D3%= !"#$%&'#()*+,#-"&&./. ())(,#0"1"!2.34.5& ())6,#7"815&9% ())+ !"#$%&%'%()*(+*,-"./)%"/0*12(3-2'%-& Maximum Load at Failure !".%00-&*6-)7() 10 Control 8 40-5(2*6-)7() 6 [N] 4 2 0 14 21 28 35 42 49 63 Days Post-Surgery 94&"):%: &"):%: !"#$%&&%'%(')&*+',--.*'/01 2'3&#)$$"4 %(')&*+',--.*'/'566& 278$*' Similarities between wound and tendon healing Thiruvoth et al. 2015. Plastic and Aesthetic Research AJ Jomas et al. 2014. Advanced Drug Delivery Review Similarities between wound and tendon healing Nichols, Best, Loiselle. 2019 Inflammation Well-regulated inflammation is beneficial -activates healing cascade -recruitment/activation of cells Excessive/ Chronic inflammation is pathological -degenerative matrix changes -fibrotic healing Benefits of Anti-inflammatory therapy is controversial Timing may be key! Generally effective at preventing excess scar formation Early inhibition decreases mechanics Delayed healing maintains mechanics Cell-type specific considerations Virchenko et al., 2004. Am J Sports Med, Geary et al. 2015. PlosOne Proliferative/ Granulation Phase • Lasts a few weeks Col3a1 ISH • Begins ~day 7 in mouse model Scar • Proliferation of ‘fibroblasts’ Tendon Tissue • Bridging on injury site • Production of ECM components (Col1/ Col3) Tendon • Rapid deposition of disorganized ECM Day 3 Day 14 Thomopoulos et al., 2009. JOR, Thomopoulos et al., 2010. JBJS, Katzel et al. 2010. JOR, Awad Lab, Loiselle Lab Remodeling Phase • Lasts many months • Begins ~day 21 in mouse model • Reorientation of ECM • Mmp-mediated remodeling Day 21 Day 28 Day 35 "(##-11'()+F-2$.%L+M+=-).#$6-+9$)$/#-+3'+5-231.6.3/+$/5+%-;35-)./0 I-/53/+4/J(%K !"#$%&'())*+,-$)./0+%-123/1- 4;2$.%-5+0).5./0+'(/#6.3/+<+16%-/06, 4/#%-$1-5+6-/53/+1.7-8+9(): !"#$%&'&$( )"*$+",&(- =.13%0$/.7-5+>?6%$#-))()$%+@$6%.?+A>B@C >?#-11.D-+>B@+E%35(#6.3/ 4/1(''.#.-/6+>B@+F-;35-)./0 B3)G8+B3)H @$6%.?+@-6$))32%36-./$1-1 >B@+E%35(#./0+B-))1 @@E+E%35(#./0+B-))1 Double-edged sword of tendon healing Matrix deposition Mechanical properties Fibrosis • Thickening and/or scarring of connective tissue • Typically in response to injury • In response to injury fibrosis= scar tissue • Excess matrix deposition • Disorganized matrix Inflammation Matrix Deposition • Exuberant healing response !"#$%&'()'*+,&'+-./%,.'01,2+&3'$-.'43#,'!!'*+$1,&,2' (-'4,-.(-'5,$6+-7 @A#B$"3C$ !%($ ?&3* ()*'$ PQ5:*5N 9&5R*K'K DEFG!H<I$ )8)')&')"8 ?)2* 9%( !"#$%&'$()*'$+!%(,-$./0$12&3$45"6$4&'7$3*&8$2"8'5"3$ / .> LF ./ .@ >. >M 9):;$%&'$()*'$+9%(,-$</0$12&3$45"6$4&'7$=>(? J**BK (&NK$O"K'APQ5:*5N Body Weight 50 * LFD 40 HFD Body Weight Fasting Blood Glucose Glucose Tolerance Test Percent Body Fat 30 50 250 600 60 * LFD * * * **** 20 40 200 HFD * 400 40 10 30 150 Body Weight (g) Weight Body 0 20 mg/dL 100 200 LFD 20 LFD HFD Body Fat [%] 10 50 Diet (g) Weight Body HFD 0 0 [mg/dL] Glucose Blood 0 0 LFD HFD LFD HFD 0 15 30 60 120 LFD HFD Diet Diet Time Post-Glucose Bolus Diet S2B*56&8T O3"KU8*V$>/.FV T2DM Impairs Tendon Healing Gliding Resistance MTP Flexion Angle Max Load at Failure 80 ** 4 LFD 50 LFD HFD ** 40 HFD 60 3 30 40 * 2 20 20 1 10 0 0 Max Load at Failure [N] 0 10 14 21 28 [A.U.] Resistance Gliding 10 14 21 28 MTP Flexion Angle [Degrees] 10 14 21 28 Days Post- Repair Days Post- Repair Days Post- Repair Col3a1 Col1a1 6 4 LFD * * HFD * 3 4 * * 2 * mRNA Expression mRNA mRNA Expression mRNA 2 1 * Relative 0 Relative 0 3 7 10 14 21 28 3 7 10 14 21 28 + Ackerman PlosOne. 2017. Days Post-Repair Days Post-Repair !"#$%&'()(*+,%-*.%/)01',%2*3)-44-05(* F4/80 7 !"#$%&'()*&+ ,-./ Non-T2DM * 6 T2DM 012345555.678 012345555.678 * * 5 !"#$%# *!"#$%# 4 * 3 * 2 01234 Relative Expression 1 * 0 7 14 21 28 Days Post-Repair 6+9):;'#< 7=">?#)@5-4AB@ &#'(")*"$+,)'(%-.)/"+'%#0"#0 1(%2%#/"$+,)'(%-.)/"+-("*"#'" &#'(")*"$3+-(%2%#/"$+-(%45#62),,)0%(7+89+,)'* &#'(")*"$3+")(27+)#0545#62),,)0%(7:+8;+,)'* Aging decreases fibrotic tendon healing (too much) Ackerman et al., JOR. 2017. Aging decreases fibrotic tendon healing (too much) No change in proliferative capacity Decreased matrix production on a per cell basis Is the cellular environment the same? Ackerman et al., JOR. 2017. 543 THE JOURNAL OF BONE & JOINT SURGERY · JBJS.ORG BIOLOGIC ASPECTS OF FLEXOR VOLUME 85-A · NUMBER 3 · MARCH 2003 TENDON LACERATION AND REPAIR ments in the treatment of these injuries. While investigations into the biology of tendon healing have shed some light on the mechanisms by which tendon tissue heals, there has been rela- tively little progress toward the biologic enhancement of the healing process after injury and repair. As a result, modulation of the process by which tendons heal remains an appealing, !"#$#%&'(&)*++,&-."#%$&/*%0'%&1*2+#%$3&4%5"#%,#6&7&895"#%,#6but not currently practicable, concept. 543 Biologic Solutions to Adhesion Formation: /:*&6*++.+2"&6';<'%*%5,&'(&5*%0'%&:*2+#%$&2"*&%'5&=*++&6:2"265*"#>*0 THE JOURNAL OF BONE & JOINT SURGERY · JBJS.ORG BIOLOGIC ASPECTS OF FLEXOR Historical Perspective 1,7,15-17 VOLUME 85-A · NUMBER 3 · MARCH 2003 TENDON LACERATION AND REPAIR It is well recognized that motion prevents scar formation . There is not a specific amount of motion that is needed, only 895"#%,#6&1*2+#%$ 4%5"#%,#6&1*2+#%$ a relative amountthat is, enough to overcome the problems ments in the treatment of these injuries.
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