Bioengineering native osteochondral architecture: from in vitro models to biological joint resurfacing
Description: Throughout life, human diarthodial joints must bear loads associated with physical activity, a process enabled by the cartilage-bone interface, or osteochondral (OC) unit. Diseases such as osteoarthritis (OA) cause pathological changes to the OC unit, involving cartilage destruction, sclerotic bone, and pain, which can ultimately necessitate total joint arthroplasty (TJA), resulting in significant restrictions in mobility and daily life activities. TJA patients face a high Lifetime Risk of Revision, emphasizing the urgent need for alternative tissue-engineered solutions.Here we aim to use natural materials to bioengineer patient-specific OC grafts that mimic the architecture, zonal organization and functional properties of native OC tissue as closely as possible. The osteochondral unit is comprised of transitions from hyaline articular cartilage, calcified cartilage zone, subchondral bone plate and subchondral cancellous bone. Using 3D computer models based on native subchondral bone architecture, a high-resolution model of the subchondral microarchitecture will be printed from a bioceramic known for its outstanding toughness, strength and osseointegrative properties. Cellular layers of hyaline and calcified cartilage will be bonded to the bioceramic base and matured in a bioreactor until matching the native tissue. The efficacy of these personalized grafts to regenerate OC lesions will be tested in an articular cartilage/subchondral bone defect model in sheep. Importantly, the implants are designed based on µCT data of the implant site, assuring an excellent anatomical match to the surrounding tissue. We hypothesize that these OC implants will be able to 1) restore the load-carrying capacity of the joint, 2) provide a mechanically stable support bed for the hyaline cartilage layer and 3) promote physiologic cartilage/bone crosstalk needed for long term joint homeostasis. Towards clinical translation, we aim to further develop the methodology to resurface human osteoarthritic joints. Adult articular chondrocytes possess poor regenerative properties, making tissue-engineered cartilage with this cell source problematic. Here, we aim to rejuvenate human adult articular chondrocytes without loss of chondrogenic phenotype, enabling them to produce functional cartilage. To do so, we will exploit gene editing to knock-in a variant of a member of the Sirtuin family, SIRT6, that is present in centenarians and has been shown to promote genome integrity, mitigate DNA damage and attenuate cellular senescence. We hypothesize that the engineered human articular chondrocytes (hART) will be protected from the oxidative-stress-induced senescence (I.e., stress-induced premature senescence, SIPS) experienced in the inflamed OA microenvironment, enabling the production of engineered autologous articular cartilage.Using these engineered autologous chondrocytes, we will create OC units to study the crosstalk between cartilage and bone layers in health and the role this crosstalk plays in the initiation of osteoarthritis. Specifically, we will study how the senescence-associated secretory phenotype (SASP) from one tissue compartment can cross the OC junction to influence the second compartment—and vice versa. Finally, the technology will be used to create the world’s first human-scale bioprostheses for large osteoarthritic defects. These studies herald new options for resurfacing osteoarthritic joints. In the long-term, we aim to reduce revision surgery by personalizing the implants according to individualized requirements, matching natural biomechanics, and avoiding materials prone to wear and failure. The methodology we will develop could one day provide robust, biocompatible solutions for OC regeneration of the aging population.
Amount: CHF 2,097,000
Funding type: research
Funder scheme: Project funding
Start date: 2024-07-01
End date: 2028-06-30
Investigator: Zenobi-Wong, Marcy
Institution: ETH Zurich – ETHZ
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Funded outputs count: 1
Funder award ID: 10000207
OpenAlex ID: G2156566027