Amazing stuff! This could be a breakthrough!
"Patient recovery from many debilitating conditions and diseases could be sped up significantly and be more effective if drugs and therapeutic molecules were delivered right to where they are needed in the body, over the entire regenerative process, and in doses finely tuned to therapeutic needs. An intriguing way to achieve this is the use of implantable, synthetically engineered, living cells that can sense injury or disease-associated conditions in their environment and flexibly respond by producing the right amount of a therapeutic molecule.
Bacteria, in particular, are promising in this regard as they can thrive in harsh physiological environments within the body, such as within infected or inflamed tissues, tissues undergoing mechanical movements, and tumors.
Some of these microbial therapies have even advanced into clinical trials to treat certain cancers, metabolic disorders, and the progression of kidney stones. However, thus far, such trials have failed, and microbes are feared to also pose significant safety risks because they cannot be contained at specific sites in the body. ...
By encapsulating a genetically engineered, therapeutic strain of E. coli bacteria within a biomaterial made from a hydrogel that was specifically designed to regulate bacterial growth and resist mechanical stresses, like those present at physically active sites in the body, the bacteria could be confined for over six months.
The E. coli bacteria were equipped with a synthetic gene circuit that allowed them to sense pathogenic Pseudomonas aeruginosa bacteria causing infections and then respond by releasing a therapeutic molecule that killed the nearby residing pathogens.
Implanted into the joints of mice next to a specialized orthopedic implant designed to help heal femoral injuries, the ILM autonomously and effectively treated infections with P. aeruginosa, a common cause of often debilitating orthopedic device infections. ..."
From the abstract of the Perspective:
"Engineered cells can sense disease and deliver drugs at a site of pathology. These living therapeutics provide localized, self-sustaining responses to environmental changes, such as inflammation and pathogenic signals, that conventional drugs cannot offer ...
A promising chassis for living therapeutics is bacteria, which can be genetically programmed to release drugs in response to an external signal. However, bacteria require physical enclosure to prevent uncontrolled spread and toxicity. Biomaterials such as hydrogels and core-shell capsules have only demonstrated short-term containment of up to 2 weeks in culture.
On page 729 of this issue, Harimoto et al. report a hydrogel scaffold with engineered stiffness and toughness that confines bacteria for up to 6 months in culture. When the system harbored bacteria producing pyocin, it cleared an infection in a mouse model of joint replacement. This could advance living therapeutics from short-lived proof-of-concept systems to durable, programmable medicines."
From the editor's summary and abstract:
"Editor’s summary
Engineered bacteria could serve as a source of long-term drug delivery, but they tend to escape confinement because of their small size and robust viability. Harimoto et al. created a polyvinyl alcohol (PVA) hydrogel matrix engineered for both high stiffness and high toughness that can contain bacteria without killing them off ... The hydrogel is used to trap engineered Escherichia coli that expresses a sense-and-respond genetic circuit designed to trigger the release of a protein antibiotic to clear Pseudomonas infection. This system was tested in vivo over a 6-month period, revealing positive treatment outcomes in a murine joint infection model. ...
Abstract
Microbes are increasingly used as living therapeutics, yet their uncontrolled dissemination in the body has remained a clinical roadblock.
Physical containment remains largely unattainable owing to eventual bacteria escape.
In this work, we present an implantable material that encapsulates and confines bacteria, wherein synthetically engineered microbes produce therapeutic payloads from within.
We developed a hydrogel scaffold with dual mechanical features: high stiffness to regulate bacterial proliferation and high toughness to resist material fracture under physiological stress.
This design achieved complete bacterial containment for 6 months and withstood multiple forms of mechanical loading that otherwise caused catastrophic material failure.
By genetically engineering embedded bacteria, we endowed the material with environmental sensing and on-demand therapeutic release capabilities and demonstrated autonomous treatment in a murine prosthetic joint infection model."
Materializing safe, on-demand living therapeutics (original news release)
Scaffolds toughen bacteria-based therapy (Perspective, no public access)
Implantable Living Materials Autonomously Deliver Therapeutics from Contained Engineered Bacteria (preprint, open access)
This illustration explains how the team designed Implantable Living Materials (ILMs) as a living therapeutic that uses an optimized hydrogel to safely contain synthetically engineered bacteria that are able to sense a pathogenic stimulus and respond to it by secreting a therapeutic protein within living organisms. The material itself is sufficiently “stiff” so that bacteria pushing against it from the inside can’t break it apart, and sufficiently “tough” to provide to protect the enclosed bacteria against external physical stresses. Combined with the synthetically engineered bacteria, the new approach becomes a safe and autonomous functioning drug delivery device.
Fig. 1 Design and mechanical characterization of Implantable Living Materials (ILMs).
Fig. 2 ILMs maintain bacterial containment during long-term culture and mechanical loading.
