Injected into the body, self-healing nanogel acts as customized long-term drug supply

February 24, 2015

These scanning electron microscopy images, taken at different magnifications, show the structure of new hydrogels made of nanoparticles interacting with long polymer chains (credit: Eric A. Appel et al./Nature Communications)

MIT chemical engineers have designed a new type of self-healing hydrogel that can be injected through a syringe to supply one or two different drugs at a time.

In theory, gels could be useful for delivering drugs for treating cancer, macular degeneration, or heart disease because they can be molded into specific shapes and designed to release their payload in a specific location over a specified time period. However, current gels are not very practical because they must be implanted surgically.

In contrast, the new gel consists of a mesh network of nanoparticles made of polymers entwined within strands of another polymer, such as cellulose.  “Now you have a gel that can change shape when you apply stress to it, and then, importantly, it can re-heal when you relax those forces. That allows you to squeeze it through a syringe or a needle and get it into the body without surgery,” says Mark Tibbitt, a postdoc at MIT’s Koch Institute for Integrative Cancer Research and one of the lead authors of a paper describing the gel in Nature Communications on Thursday Feb. 19.

Koch Institute postdoc Eric Appel is also a lead author of the paper, and the paper’s senior author is Robert Langer, the David H. Koch Institute Professor at MIT.

Another limitation of hydrogels for biomedical uses — such as making soft contact lenses — is that they are traditionally formed by irreversible chemical linkages between polymers, so their shape cannot easily be altered.

How to create a self-assembling gel

So the MIT team set out to create a gel that could survive strong mechanical forces, known as shear forces, yet capable of reforming itself. Other researchers have created such gels by engineering proteins that self-assemble into hydrogels, but this approach requires complex biochemical processes. The MIT team wanted to design something simpler.

The MIT approach relies on a combination of two readily available components. One is a type of nanoparticle formed of PEG-PLA copolymers, first developed in Langer’s lab decades ago and now commonly used to package and deliver drugs. To form the new hydrogel, the researchers mixed these particles with a polymer — in this case, cellulose.

Each polymer chain forms weak bonds with many nanoparticles, producing a loosely woven lattice or network of polymers and nanoparticles. Because each attachment point is fairly weak, the bonds are able to break apart under mechanical stress, such as when injected through a syringe. When these shear forces are over, the polymers and nanoparticles reassemble, forming new attachments with different partners and healing the gel.

Using two components to form the gel also gives the researchers the opportunity to deliver two different drugs at the same time. PEG-PLA nanoparticles have an inner core that is ideally suited to carry hydrophobic (water-incompatible) small-molecule drugs, which include many chemotherapy drugs. Meanwhile, the polymers, which exist in a watery solution, can carry hydrophilic (water-compatible) molecules such as proteins, including antibodies and growth factors.

Long-term drug delivery

In this study, the researchers showed that the gels survived injection under the skin of mice and successfully released two drugs, one hydrophobic and one hydrophilic, over several days.

This type of gel offers an important advantage over injecting a liquid solution of drug-delivery nanoparticles: Such a solution will immediately disperse throughout the body, while the gel stays in place after injection, allowing the drug to be targeted to a specific tissue and avoiding toxic reactions elsewhere. Furthermore, the properties of each gel component can be tuned so the drugs they carry are released at different rates, allowing them to be tailored for different uses.

Treating eye, heart, and cancer issues

The researchers are now looking into using the gel to deliver anti-angiogenesis (anti-blood-vessel-forming) drugs to treat macular degeneration. Currently, patients receive these drugs, which cut off the growth of blood vessels that interfere with sight, as an injection into the eye once a month (try not to visualize that). The MIT team envisions that the new gel could be programmed to deliver these drugs over several months, reducing the frequency of injections.

Another potential application for the gels is delivering drugs, such as growth factors, that could help repair damaged heart tissue after a heart attack.

The researchers are also pursuing the possibility of using this gel to deliver cancer drugs to kill tumor cells that get left behind after surgery. In that case, the gel would be loaded with a chemical that lures cancer cells toward the gel, as well as a chemotherapy drug that would kill them. This could help eliminate the residual cancer cells that often form new tumors following surgery.

“Removing the tumor leaves behind a cavity that you could fill with our material, which would provide some therapeutic benefit over the long term in recruiting and killing those cells,” Appel says. “We can tailor the materials to provide us with the drug-release profile that makes it the most effective at actually recruiting the cells.”

The research was funded by the Wellcome Trust, the Misrock Foundation, the Department of Defense, and the National Institutes of Health.

Abstract of Self-assembled hydrogels utilizing polymer–nanoparticle interactions

Mouldable hydrogels that flow on applied stress and rapidly self-heal are increasingly utilized as they afford minimally invasive delivery and conformal application. Here we report a new paradigm for the fabrication of self-assembled hydrogels with shear-thinning and self-healing properties employing rationally engineered polymer–nanoparticle (NP) interactions. Biopolymer derivatives are linked together by selective adsorption to NPs. The transient and reversible interactions between biopolymers and NPs enable flow under applied shear stress, followed by rapid self-healing when the stress is relaxed. We develop a physical description of polymer–NP gel formation that is utilized to design biocompatible gels for drug delivery. Owing to the hierarchical structure of the gel, both hydrophilic and hydrophobic drugs can be entrapped and delivered with differential release profiles, both in vitro and in vivo. The work introduces a facile and generalizable class of mouldable hydrogels amenable to a range of biomedical and industrial applications.




Attacking Alzheimer’s with ultrasound

February 24, 2015

The plaque abnormalities on untreated transgenic mice (left) and the brain of a transgenic mouse that has been treated with MR imaging-guided focused ultrasound (right), showing reduced plaque (credit: Kullervo Hynynen, Sunnybrook Research Institute)


For the first time, researchers have reversed some of the symptoms of Alzheimer’s disease* in mice using magnetic resonance (MR) imaging-guided focused ultrasound.

As KurzweilAI reported in 2012, Sunnybrook Research Institute scientists used MR imaging-guided focused ultrasound to temporarily open the blood-brain barrier (BBB), allowing for more effective delivery of drugs to the brain. The method uses a microbubble contrast agent. The microbubbles vibrate when they pass through the ultrasound beam, temporarily creating an opening in the BBB for the drugs to pass through. In addition, this combination of ultrasound and microbubbles has been shown to increase the number of new neurons and the dendrite length.

In the new study, Kullervo Hynynen, Ph.D., a medical physicist at Sunnybrook Research Institute, and his collaborators studied the effects of using MR imaging-guided focused ultrasound on the hippocampus of transgenic (TgCRND8) mice.

Mice with this genetic variant have increased plaque on their hippocampus, the part of the brain that helps convert information from short-term to long-term memory; they also display symptoms similar to Alzheimer’s such as memory impairment and learning reversal. That allows these transgenic mice to be used as an animal model for Alzheimer’s disease.

Improved cognition and spatial learning

The researchers used MR imaging-guided focused ultrasound with microbubbles to open the BBB and treat the hippocampus of the mice. The hippocampus is divided into two parts, one in each hemisphere of the brain. They found the treatment led to improvements in cognition and spatial learning in the transgenic mice, potentially caused by reduced plaque and increased neuronal plasticity due to the focused ultrasound treatment.

They found no tissue damage or negative behavioral changes in the mice due to the treatments in either the transgenic mice or the control (nontransgenic) mice. Both groups of mice benefited from increased neuronal plasticity, which confirms the previous research on the effects of MR imaging-guided focused ultrasound on plasticity in healthy mice.

How it works

According to the Radiology paper, the investigators in previous studies have suggested two potential mechanisms for plaque reduction:

  • Opening of the BBB permits the entry of endogenous immunoglobuline G and immunoglobulin M from the periphery into the brain, which assists with plaque clearance.
  • MR imaging-guided focused ultrasound causes mild activation of astrocytes and microglia, which were shown to internalize amyloid and contribute to plaque reduction. These potential mechanisms are likely to also contribute to the reduced plaque observed in this study.

Next steps

“The results are an exciting step in the search for Alzheimer’s treatments,” said Steven Krosnick, M.D., Program Director for Image-Guided Interventions at the National Institute of Biomedical Imaging and Bioengineering at NIH, “but there is more to be done. There are limitations on the memory tests that can be done on mice, and human cognition is significantly more complex.

“Hopefully these results will open doors to more research on how MR imaging-guided focused ultrasound could benefit cognition and perhaps be magnified by using other therapeutics in conjunction with this method.”

This research was supported in part by the National Institute of Biomedical Imaging and Bioengineering award #EB003268

* An estimated 5.2 million Americans suffer from Alzheimer’s. It is the sixth leading cause of death in the United States and there is currently no treatment for the disease.

Abstract for Alzheimer disease in a mouse model: MR imaging–guided focused ultrasound targeted to the hippocampus opens the blood-brain barrier and improves pathologic abnormalities and behavior

Purpose: To validate whether repeated magnetic resonance (MR) imaging–guided focused ultrasound treatments targeted to the hippocampus, a brain structure relevant for Alzheimer disease (AD), could modulate pathologic abnormalities, plasticity, and behavior in a mouse model.

Materials and Methods: All animal procedures were approved by the Animal Care Committee and are in accordance with the Canadian Council on Animal Care. Seven-month-old transgenic (TgCRND8) (Tg) mice and their nontransgenic (non-Tg) littermates were entered in the study. Mice were treated weekly with MR imaging–guided focused ultrasound in the bilateral hippocampus (1.68 MHz, 10-msec bursts, 1-Hz burst repetition frequency, 120-second total duration). After 1 month, spatial memory was tested in the Y maze with the novel arm prior to sacrifice and immunohistochemical analysis. The data were compared by using unpaired t tests and analysis of variance with Tukey post hoc analysis.

Results: Untreated Tg mice spent 61% less time than untreated non-Tg mice exploring the novel arm of the Y maze because of spatial memory impairments (P < .05). Following MR imaging–guided focused ultrasound, Tg mice spent 99% more time exploring the novel arm, performing as well as their non-Tg littermates. Changes in behavior were correlated with a reduction of the number and size of amyloid plaques in the MR imaging–guided focused ultrasound– treated animals (P < .01). Further, after MR imaging–guided focused ultrasound treatment, there was a 250% increase in the number of newborn neurons in the hippocampus (P < .01). The newborn neurons had longer dendrites and more arborization after MR imaging– guided focused ultrasound, as well (P < .01).

Conclusion: Repeated MR imaging–guided focused ultrasound treatments led to spatial memory improvement in a Tg mouse model of AD. The behavior changes may be mediated by decreased amyloid pathologic abnormalities and increased neuronal plasticity.



Tiny soft robotic hands with magnetic nanoparticles could improve cancer diagnostics, drug delivery

February 11, 2015

Schematic diagram illustrating reversible self-folding of soft microgrippers in response to temperature (credit: Joyce C. Breger et al./ACS Appl.Mater.Interfaces)

“Soft robotics” researchers have developed a flexible, microscopic hand-like gripper that could help doctors perform remotely guided surgical procedures, biopsies, and someday deliver therapeutic drugs to hard-to-reach places.

David H. Gracias at The Johns Hopkins University and colleagues note that many robotic tools require cords to provide power to generate their movements, adding to the bulk of robots and limiting the spaces they can access.

To address this constraint, scientists have turned to hydrogels. These soft materials can swell in response to changes in temperature, acidity or light, providing energy to carry out tasks without being tethered to a power source.

However, hydrogels are too floppy for some applications, so the group combined the hydrogels with a stiff biodegradable polymer, making the microhands strong enough to wrap around and remove cells. The team then sought a way to control where the grippers go once deployed in the body.

The researchers incorporated ferromagnetic nanoparticles in the materials so they could guide the microhands with a magnetic probe. That allows for microassembly or microengineering of soft or biological parts and gives surgeons the ability to remotely direct where biopsies are taken.

Also, Gracias says that the use of soft materials highlights the possibility of creating biodegradable, miniaturized surgical tools that can safely dissolve in the body.

The work was funded by the National Science Foundation and the National Institutes of Health.

Abstract of Self-Folding Thermo-Magnetically Responsive Soft Microgrippers

Hydrogels such as poly(N-isopropylacrylamide-co-acrylic acid) (pNIPAM-AAc) can be photopatterned to create a wide range of actuatable and self-folding microstructures. Mechanical motion is derived from the large and reversible swelling response of this cross-linked hydrogel in varying thermal or pH environments. This action is facilitated by their network structure and capacity for large strain. However, due to the low modulus of such hydrogels, they have limited gripping ability of relevance to surgical excision or robotic tasks such as pick-and-place. Using experiments and modeling, we design, fabricate, and characterize photopatterned, self-folding functional microgrippers that combine a swellable, photo-cross-linked pNIPAM-AAc soft-hydrogel with a nonswellable and stiff segmented polymer (polypropylene fumarate, PPF). We also show that we can embed iron oxide (Fe2O3) nanoparticles into the porous hydrogel layer, allowing the microgrippers to be responsive and remotely guided using magnetic fields. Using finite element models, we investigate the influence of the thickness and the modulus of both the hydrogel and stiff polymer layers on the self-folding characteristics of the microgrippers. Finally, we illustrate operation and functionality of these polymeric microgrippers for soft robotic and surgical applications.