TEndons are small but strong linkers between bones and muscles. Repairing tendons when injured is not an easy task. Alaina LoiselOrthopedic researchers at the University of Rochester Medical Center are developing a new treatment for tendon injuries.
Her recent works include: scientific progress It addresses a major challenge in tendon treatment: getting the drug to the tendon itself.1 In an interview with scientistLoisel explained how carefully designed nanoparticles can improve targeted drug delivery to tendons such as lesions.
Alaina Loisel uses nanoparticle delivery to develop anti-inflammatory drugs that target tendons.
Lin Tseng
Why are tendon injuries so difficult to treat?
At our hospital, we mainly treat acute trauma. Something like this happened to me before when I cut my hand while slicing a bagel. Avocados are now mainstream. Surgical repair is pretty standard, but tendons are tricky because the body has to create a matrix in order to repair the tissue. Often, the tendon becomes overworked and produces too much matrix, causing the patient to develop excess scar tissue and the tendon to lose some of its function. Almost all of my career has involved identifying strategies to promote tendon healing.
How can new drugs help promote tendon healing?
There’s a Goldilocks-like sweet spot. You want to create enough matrix to repair the tendon, but you don’t want to create large, bulky scar tissue that won’t migrate well. That is the goal of therapy. Since inflammation is the first step in healing and can lead to excessive scarring, many people have tried anti-inflammatory treatments.
However, these studies are not as effective and I wonder if that is partially related to how effectively the treatment is reaching the tendon. In our study, we found that these drugs do not successfully reach tendons when administered systemically. That was the motivation for our recent study. We needed a way to actually deliver a promising therapeutic to the tendon relatively efficiently.
What strategy did you use to deliver the drug to the tendon?
Although my research has always focused on the fundamental mechanisms of healing to identify therapeutic candidates, my team has not given much consideration to the actual practicalities of drug delivery. This is where the power of collaboration comes into play. Daniel Benoit’s lab at the University of Oregon is developing nanoparticles as drug delivery systems. They use different ligands to promote nanoparticle homing to different tissues.
One example of a ligand developed by Benoit for nanoparticles is a tartrate-resistant acid phosphatase (TRAP)-binding peptide, which has high affinity for regions of TRAP activity.2 TRAP plays a role in bone remodeling and is therefore an excellent drug delivery system for healing fractures. I have always been impressed with the system and wondered if it would be possible to attach some nanoparticles within the tendon to more effectively return the nanoparticles to the tendon. Through spatial transcriptome profiling, we found that TRAP is highly expressed in tendons.3
How have you used nanoparticles as part of your therapeutic approach?
We used an S100A4 inhibitor. This is a molecule that probably plays a role in inflammation, but is also significantly involved in matrix deposition. We put the drug into nanoparticles and injected them into mice with tendon injuries. If the tendon heals well, it should become stronger and have a better range of motion. In our study, we saw improvements in both of these outcomes, which was really great and gave us hope about how effective this treatment could be.
What are the next steps to develop this drug delivery approach?
Ultimately, our goal is to build systems that can deliver improved patient outcomes, so we are currently working to address the challenges of scaling up to large preclinical models and clinical trials. I’m here. We also have safety studies showing that these nanoparticles are well tolerated and removed. No significant off-target effects are observed.
I think we’re in really exciting times. Previously, there were technology limitations when searching for the cells and processes involved in healing. But now, with the increased availability of tools such as single-cell sequencing and spatial transcriptomics, we have a very powerful dataset that can be leveraged to comprehensively understand this process. From there, it’s just a matter of prioritizing the most important steps and identifying translational ways to target those processes.
This interview has been condensed and edited for clarity.
