With a goal of treating worn, arthritic hips without extensive surgery to replace them, scientists have programmed stem cells to grow new cartilage on a 3-D template shaped like the ball of a hip joint. What’s more, using gene therapy, they have activated the new cartilage to release anti-inflammatory molecules to fend off a return of arthritis.
The technique, demonstrated in a collaborative effort between Washington University School of Medicine in St. Louis and Cytex Therapeutics Inc. in Durham, N.C., is described July 18 in Proceedings of the National Academy of Sciences.
The discovery one day may provide an alternative to hip-replacement surgery, particularly in younger patients. Doctors are reluctant to perform such operations in patients under age 50 because prosthetic joints typically last for less than 20 years. A second joint-replacement surgery to remove a worn prosthetic can destroy bone and put patients at risk for infection.
The technique uses a 3-D, biodegradable synthetic scaffold that Guilak and his team developed. The scaffold, molded into the precise shape of a patient’s joint, is covered with cartilage made from the patient’s own stem cells taken from fat beneath the skin. The scaffold then can be implanted onto the surface of an arthritic hip, for example. Resurfacing the hip joint with “living” tissue is designed to ease arthritis pain, and delay or even eliminate the need for joint-replacement surgery in some patients.
Additionally, by inserting a gene into the newly grown cartilage and activating it with a drug, the gene can orchestrate the release of anti-inflammatory molecules to fight a return of arthritis, which usually is what triggers such joint problems in the first place.
Washington University biomedical engineering PhD student Ali Ross and Farshid Guilak, PhD, a professor of orthopedic surgery, show a container with a prototype of a living hip replacement. The scientists have coaxed stem cells to grow into new cartilage on a 3-D template shaped like the ball of a hip joint.
The 3-D scaffold is built using a weaving pattern that gives the device the structure and properties of normal cartilage. Franklin Moutos, PhD, vice president of technology development at Cytex, explained that the unique structure is the result of approximately 600 biodegradable fiber bundles woven together to create a high-performance fabric that can function like normal cartilage.
“As evidence of this, the woven implants are strong enough to withstand loads up to 10 times a patient’s body weight, which is typically what our joints must bear when we exercise,” Moutos said.
Currently, there are about 30 million Americans who have diagnoses of osteoarthritis, and data suggest that the incidence of osteoarthritis is on the rise. That number includes many younger patients — ages 40 to 65 — who have limited treatment options because conservative approaches haven’t worked and they are not yet candidates for total joint replacement because of their ages.
Bradley Estes, PhD, vice president of research and development at Cytex, noted, “We envision in the future that this population of younger patients may be ideal candidates for this type of biological joint replacement.”
Whereas some success has been realized treating isolated, focal defects or lesions of articular cartilage, the complete resurfacing of synovial joints remains an important challenge for the treatment of osteoarthritis. Here, we develop an anatomically shaped, functional cartilage construct based on a 3D woven scaffold that can provide for total joint resurfacing, with capabilities for tunable and inducible production of anticytokine therapy to protect diseased or injured joints from pathologic inflammation. An important advance of this work is the incorporation of a technique for scaffold-mediated viral gene delivery for overexpression of antiinflammatory molecules within the joint. This approach provides a foundation for total biological cartilage resurfacing to treat end-stage osteoarthritis for young patients, who currently have few therapeutic options.
Biological resurfacing of entire articular surfaces represents an important but challenging strategy for treatment of cartilage degeneration that occurs in osteoarthritis. Not only does this approach require anatomically sized and functional engineered cartilage, but the inflammatory environment within an arthritic joint may also inhibit chondrogenesis and induce degradation of native and engineered cartilage. The goal of this study was to use adult stem cells to engineer anatomically shaped, functional cartilage constructs capable of tunable and inducible expression of antiinflammatory molecules, specifically IL-1 receptor antagonist (IL-1Ra). Large (22-mm-diameter) hemispherical scaffolds were fabricated from 3D woven poly(ε-caprolactone) (PCL) fibers into two different configurations and seeded with human adipose-derived stem cells (ASCs). Doxycycline (dox)-inducible lentiviral vectors containing eGFP or IL-1Ra transgenes were immobilized to the PCL to transduce ASCs upon seeding, and constructs were cultured in chondrogenic conditions for 28 d. Constructs showed biomimetic cartilage properties and uniform tissue growth while maintaining their anatomic shape throughout culture. IL-1Ra–expressing constructs produced nearly 1 µg/mL of IL-1Ra upon controlled induction with dox. Treatment with IL-1 significantly increased matrix metalloprotease activity in the conditioned media of eGFP-expressing constructs but not in IL-1Ra–expressing constructs. Our findings show that advanced textile manufacturing combined with scaffold-mediated gene delivery can be used to tissue engineer large anatomically shaped cartilage constructs that possess controlled delivery of anticytokine therapy. Importantly, these cartilage constructs have the potential to provide mechanical functionality immediately upon implantation, as they will need to replace a majority, if not the entire joint surface to restore function.
Cytex’s bio-artificial cartilage mimics the mechanical and biological properties of natural cartilage. Cytex has two products currently in pre-clinical in-vivo studies.
Cartilage Resurfacing in the Hip
Cytex’s bio-artificial cartilage implant is being developed to resurface an arthritic hip with a material that immediately provides the functionality of cartilage and uses the latest tissue engineering strategies (such as stem cell therapies) to regrow the patient’s natural cartilage tissues. We envision a much simpler surgery than is currently available via hip arthroplasty. This will also provide relief for patients who are not good candidates for total joint replacement and who are left to manage chronic pain through pharmaceuticals.
Cartilage Repair in the Knee
Another application currently in development focuses on the repair of cartilage defects in the knee – both large and small. The Cytex repair implant provides flexibility in shape and size, mimics the strength and smoothness of articular cartilage, and can be used in conjunction with current techniques such as microfracture or stem cell seeding to promote long- term cartilage regeneration.
Other envisioned applications for this technology are cartilage products for shoulders (in research) and other joints. Cytex is also conducting research to develop applications for tendon injuries and defects.
- Joint resurfacing with Cytex’s bioartificial cartilage eliminates the underlying cause of arthritis, thereby eliminating joint pain and enabling the patient to resume normal physical activity.
- Provides a surgical therapy for patients who are not candidates for total joint replacement surgery, but have failed more conservative treatments.
Advantages Over Alternative Treatments:
- First available joint surface repair solution that restores native tissue function across large areas of the joint surface.
- A simplified surgical approach that allows quick recovery and mobility.
- Smart textiles engineered to mimic the principal mechanical properties of articular cartilage.
- Tissue engineering technologies are incorporated to prompt long-term restoration of the joint’s native cartilage.
- Minimal risk of body rejecting the bio-artificial cartilage.
SOURCES – Cytex Therapeutics, Washington University, PNAS