Advanced glycation end-products: Mechanics of aged collagen from molecule to tissue.
Concurrent with a progressive loss of regenerative capacity, connective tissue aging is characterized by a progressive accumulation of Advanced Glycation End-products (AGEs). Besides being part of the typical aging process, type II diabetics are particularly affected by AGE accumulation due to abnormally high levels of systemic glucose that increases the glycation rate of long-lived proteins such as collagen. Although AGEs are associated with a wide range of clinical disorders, the mechanisms by which AGEs contribute to connective tissue disease in aging and diabetes are still poorly understood. The present study harnesses advanced multiscale imaging techniques to characterize a widely employed in vitro model of ribose induced collagen aging and further benchmarks these data against experiments on native human tissues from donors of different age. These efforts yield unprecedented insight into the mechanical changes in collagen tissues across hierarchical scales from molecular, to fiber, to tissue-levels. We observed a linear increase in molecular spacing (from 1.45nm to 1.5nm) and a decrease in the D-period length (from 67.5nm to 67.1nm) in aged tissues, both using the ribose model of in vitro glycation and in native human probes. Multiscale mechanical analysis of in vitro glycated tendons strongly suggests that AGEs reduce tissue viscoelasticity by severely limiting fiber-fiber and fibril-fibril sliding. This study lays an important foundation for interpreting the functional and biological effects of AGEs in collagen connective tissues, by exploiting experimental models of AGEs crosslinking and benchmarking them for the first time against endogenous AGEs in native tissue.
Department of Orthopedics, Balgrist University Hospital, University of Zurich, 8008 Zurich, Switzerland; Institute for Biomechanics, ETH Zurich, 8093 Zurich, Switzerland; Department of Electronics, Information and Bioengineering, Politecnico di Milano, Piazza Leonardo da Vinci 32, 20133 Milano, Italy.
Alfonso
A
Gautieri
Department of Orthopedics, Balgrist University Hospital, University of Zurich, 8008 Zurich, Switzerland; Institute for Biomechanics, ETH Zurich, 8093 Zurich, Switzerland.
Fabian S
FS
Passini
Department of Orthopedics, Balgrist University Hospital, University of Zurich, 8008 Zurich, Switzerland; Institute for Biomechanics, ETH Zurich, 8093 Zurich, Switzerland.
Unai
U
Silván
Paul Scherrer Institute, 5232 Villigen, Switzerland.
Manuel
M
Guizar-Sicairos
Department of Knee Orthopedic and Sports Traumatology Unit, Humanitas Research Hospital, 20089 Rozzano, Italy.
Giulia
G
Carimati
Department of Knee Orthopedic and Sports Traumatology Unit, Humanitas Research Hospital, 20089 Rozzano, Italy.
Piero
P
Volpi
IRCCS Ist Ortoped Galeazzi, Cell & Tissue Engineering Lab, 20161 Milan, Italy; Regenerative Medicine Technologies Lab, Ente Ospedaliero Cantonale, Lugano 6900, Switzerland; Swiss Institute for Regenerative Medicine, Lugano 6900, Switzerland; Cardiocentro Ticino, Lugano 6900, Switzerland.
Matteo
M
Moretti
Sports Traumatology and Arthroscopic Surgery Unit, IRCCS Galeazzi Orthopedic Institute, Milan 20161, Italy Cell and Tissue Engineering Lab, IRCCS Galeazzi Orthopedic Institute, Milan 20161, Italy.
Herbert
H
Schoenhuber
Department of Electronics, Information and Bioengineering, Politecnico di Milano, Piazza Leonardo da Vinci 32, 20133 Milano, Italy.
Alberto
A
Redaelli
Department of Orthopedics, Balgrist University Hospital, University of Zurich, 8008 Zurich, Switzerland.
Martin
M
Berli
Department of Orthopedics, Balgrist University Hospital, University of Zurich, 8008 Zurich, Switzerland; Institute for Biomechanics, ETH Zurich, 8093 Zurich, Switzerland. Electronic address: jsnedeker@research.balgrist.ch.
Jess G
JG
Snedeker
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001696:Biomechanical Phenomena; D016022:Case-Control Studies; D003094:Collagen / Q000302:isolation & purification / Q000378:metabolism* / Q000648:ultrastructure; D003920:Diabetes Mellitus / Q000378:metabolism* / Q000473:pathology; D005109:Extracellular Matrix / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000494:pharmacology; D017127:Glycation End Products, Advanced / Q000494:pharmacology*; D006031:Glycosylation; D006801:Humans; D008297:Male; D008875:Middle Aged; D051381:Rats; D012266:Ribose / Q000494:pharmacology; D053838:Scattering, Small Angle; D013623:Tail / Q000737:chemistry; D013710:Tendons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D014783:Viscosity; D014961:X-Ray Diffraction
D017127:Glycation End Products, Advanced; D012266:Ribose; D003094:Collagen; D005947:Glucose
Advanced glycation end-products; Aging; Collagen mechanics; Functional microscopy; Small-angle X-ray scattering