Direct MRI of Collagen
Curation statements for this article:-
Curated by eLife
eLife Assessment
This fundamental work substantially advances our understanding of a major research question: whether collagen can be directly imaged with MRI. The evidence supporting the conclusion is compelling, with methods, data, and analyses that are more rigorous than those currently considered state-of-the-art. The work will be of high interest to MR physicists and clinicians, as collagen is the most abundant protein in the human body and plays an essential role in health.
This article has been Reviewed by the following groups
Discuss this preprint
Start a discussion What are Sciety discussions?Listed in
- Evaluated articles (eLife)
Abstract
Collagen is the most abundant protein in the human body and has an important role in healthy tissue as well as in a range of prevalent diseases. Medical research and diagnostics hence call for means of mapping collagen in vivo. Magnetic resonance imaging (MRI) is a natural candidate for this task, offering full 3D capability and versatile contrast non-invasively. However, collagen has so far been invisible to MRI due to extremely short lifetime of its resonances. Here, we report the direct imaging of collagen in vivo by magnetic resonance on the microsecond scale. The dynamics of resonance signals from collagen were first assessed in samples of bovine tendon and cortical bone. On this basis, imaging was performed at echo times down to 10 microseconds, yielding collagen-specific depiction by echo subtraction. The same approach was then extended for use in vivo, enabling direct collagen imaging of a human forearm. This capability suggests significant promise for biomedical science and clinical use.
Significance statement
Collagen is a prevalent protein in the human body that plays a critical role in maintaining tissue integrity. Collagen-related conditions such as arthritis and fibrosis are widespread and have thus warranted the extensive investigation of the protein. Until now, however, non-invasive depiction of collagen using magnetic resonance imaging (MRI) has been considered infeasible because MR signals from collagen decay too quickly to be detected. In this work, dedicated hardware and methodology targeting such signals are employed to enable direct visualization of collagen with MRI. The proposed technique presents a novel approach to study the structure and distribution of collagen in the body, with a range of potential applications in medical diagnostics, drug testing, and tissue engineering.
Article activity feed
-
eLife Assessment
This fundamental work substantially advances our understanding of a major research question: whether collagen can be directly imaged with MRI. The evidence supporting the conclusion is compelling, with methods, data, and analyses that are more rigorous than those currently considered state-of-the-art. The work will be of high interest to MR physicists and clinicians, as collagen is the most abundant protein in the human body and plays an essential role in health.
-
Reviewer #1 (Public review):
Summary:
The aim of this work is to directly image collagen in tissue using a new MRI method with positive contrast. The work presents a new MRI method that allows very short, powerful radio frequency (RF) pulses and very short switching times between transmission and reception of radio frequency signals.
Strengths:
The experiments with and without the removal of 1H hydrogen, which is not firmly bound to collagen, on tissue samples from tendons and bones, are very well suited to prove the detection of direct hydrogen signals from collagen. The new method has great potential value in medicine, as it allows for better investigation of ageing processes and many degenerative diseases in which functional tissue is replaced by connective tissue (collagen).
Weaknesses:
It is clear that, due to the relatively long …
Reviewer #1 (Public review):
Summary:
The aim of this work is to directly image collagen in tissue using a new MRI method with positive contrast. The work presents a new MRI method that allows very short, powerful radio frequency (RF) pulses and very short switching times between transmission and reception of radio frequency signals.
Strengths:
The experiments with and without the removal of 1H hydrogen, which is not firmly bound to collagen, on tissue samples from tendons and bones, are very well suited to prove the detection of direct hydrogen signals from collagen. The new method has great potential value in medicine, as it allows for better investigation of ageing processes and many degenerative diseases in which functional tissue is replaced by connective tissue (collagen).
Weaknesses:
It is clear that, due to the relatively long time intervals between RF excitation and signal readout, standard hardware in whole-body MRI systems can only be used to examine surrounding water and not hydrogen bound to collagen molecules.
-
Reviewer #2 (Public review):
Summary:
This work presents direct magnetic resonance imaging (MRI) of collagen, which is not possible with conventional MRI or other tomographic imaging modalities.
Strengths:
The experimental work is impressive, and the presentation of results is clear and convincing. Through a series of thoughtfully prepared experiments, I found the evidence that the images reflect direct measurements of collagen to be highly compelling.
Due to the technical demands, direct collagen imaging is unlikely to become widespread for routine clinical work, at least not anytime soon. That said, this work is nonetheless transformative and will likely be highly significant for research and perhaps clinical trials.
-
Reviewer #3 (Public review):
The paper is well written and well presented. The topic is important, and its significance is explained succinctly and accurately. I am only capable of reviewing the clinical aspects of this work, which is very largely technical in nature. Several clinical points are worth considering:
(1) Tendons typically display large magic angle effects as a result of their highly ordered collagen structure (cortical bone much less so), and so it would have been of interest to know what orientation the tendons had to B 0 (in vitro and in vivo). This could affect the signal level at the longer echo time and thus the signal on the subtracted images.
(2) The in vivo transverse image looks about mid-forearm, where tendons are not prominent. A transverse image of the lower forearm, where there is an abundance of tendons, …
Reviewer #3 (Public review):
The paper is well written and well presented. The topic is important, and its significance is explained succinctly and accurately. I am only capable of reviewing the clinical aspects of this work, which is very largely technical in nature. Several clinical points are worth considering:
(1) Tendons typically display large magic angle effects as a result of their highly ordered collagen structure (cortical bone much less so), and so it would have been of interest to know what orientation the tendons had to B 0 (in vitro and in vivo). This could affect the signal level at the longer echo time and thus the signal on the subtracted images.
(2) The in vivo transverse image looks about mid-forearm, where tendons are not prominent. A transverse image of the lower forearm, where there is an abundance of tendons, might have been preferable.
(3) The in vivo images show the interosseous membrane as a high signal on both the shorter and longer TE images. The structure contains ordered collagen with fibres at different oblique angles to the radius and ulnar, and thus potentially to B 0. Collagen fibres may have been at an orientation towards the magic angle, and this may account for the high signal on the longer TE image and the low signal on the subtracted image.
(4) Some of the signals attributed to the muscle may be from an attachment of the muscle to the aponeurosis.
(5) There is significant collagen in subcutaneous tissues, so the designation "skin" may more correctly be "skin and subcutaneous tissue".
(6) Cortical bone is very heterogeneous, with boundaries between hard bone and soft tissue with significant susceptibility differences between the two across a small distance. This might be another mechanism for ultrashort T 2 * tissue values in addition to the presence of collagen. The two effects might be distinguished by also including a longer TE spin echo acquisition.
Solid cortical bone may also have an ultrashort T 2 * in its own right.
(7) It may be worth noting that in disease T 2 * may be increased. As a result, the subtraction image may make abnormal tissue less obvious than normal tissue. Magic angle effects may also produce this appearance.
(8) It may be worth distinguishing fibrous connective tissue (loose or dense), which may be normal or abnormal, from fibrosis, which is an abnormal accumulation of fibrous connective tissue in damaged tissue. Fibrosis typically has a longer T 2 initially and decreases its T 2 * over time. In places, the context suggests that fibrous connective tissue may be more appropriate than fibrosis.
Overall, the paper appears very well constructed and describes thoughtful and important work.
-
