Nordihydroguaiaretic acid microparticles are effective in the treatment of osteoarthritis.

Several disease-modifying osteoarthritis (OA) drugs have emerged, but none have been approved for clinical use due to their systemic side effects, short half-life, and rapid clearance from the joints. Nordihydroguaiaretic acid (NDGA), a reactive oxygen species (ROS) scavenger and autophagy inducer, could be a potential treatment for OA. In this report, we show for the first time that sustained delivery of NDGA through polymeric microparticles maintains therapeutic concentrations of drug in the joint and ameliorates post-traumatic OA (PTOA) in a mouse model. In vitro treatment of oxidatively stressed primary chondrocytes from OA patients using NDGA-loaded poly(lactic-co-glycolic acid) (PLGA) microparticles (NDGA-MP) inhibited 15-lipoxygenase, induced autophagy, prevented chondrosenescence, and sustained matrix production. In vivo intra-articular delivery of NDGA-MP was non-toxic and had prolonged retention time (up to 35 days) in murine knee joints. Intra-articular therapy using NDGA-MP effectively reduced cartilage damage and reduced pain in the surgery-induced PTOA mouse model. Our studies open new avenues to modulate the immune environment and treat post-traumatic OA using ROS quenchers and autophagy inducers.

Teaming up to overcome challenges toward translation of new therapeutics for osteoarthritis.

As a leading global cause of musculoskeletal-related disability, osteoarthritis (OA) represents a public health urgency. Understanding of disease pathogenesis has advanced substantially in the past decade, yet no disease-modifying therapeutics have advanced to the clinic. To address this challenge, the CARE-AP (Cartilage Repair strategies to alleviate Arthritis Pain) collaborative research team was convened to bring together relevant multidisciplinary expertise and perspectives from across the VA research community nationwide. The first CARE-AP Annual Research Symposium took place (virtually) in February 2022 with roughly 90 participants. A number of innovative and therapeutic strategies were discussed, including siRNA approaches coupled with novel nanoparticle-based delivery systems, cellular engineering approaches to develop reparative cells that can probe the joint environment and respond to disease-specific cues, and novel biofabrication techniques to improve tissue engineering and effect "biological joint replacement." In addition, challenges and advances in rehabilitation approaches, imaging outcomes, and clinical studies were presented, which were integrated into a framework of recommendations for running "preclinical trials" to improve successful clinical translation.

Leveraging 3D Bioprinting and Photon-Counting Computed Tomography to Enable Noninvasive Quantitative Tracking of Multifunctional Tissue Engineered Constructs.

3D bioprinting is revolutionizing the fields of personalized and precision medicine by enabling the manufacturing of bioartificial implants that recapitulate the structural and functional characteristics of native tissues. However, the lack of quantitative and noninvasive techniques to longitudinally track the function of implants has hampered clinical applications of bioprinted scaffolds. In this study, multimaterial 3D bioprinting, engineered nanoparticles (NPs), and spectral photon-counting computed tomography (PCCT) technologies are integrated for the aim of developing a new precision medicine approach to custom-engineer scaffolds with traceability. Multiple CT-visible hydrogel-based bioinks, containing distinct molecular (iodine and gadolinium) and NP (iodine-loaded liposome, gold, methacrylated gold (AuMA), and Gd2 O3 ) contrast agents, are used to bioprint scaffolds with varying geometries at adequate fidelity levels. In vitro release studies, together with printing fidelity, mechanical, and biocompatibility tests identified AuMA and Gd2 O3 NPs as optimal reagents to track bioprinted constructs. Spectral PCCT imaging of scaffolds in vitro and subcutaneous implants in mice enabled noninvasive material discrimination and contrast agent quantification. Together, these results establish a novel theranostic platform with high precision, tunability, throughput, and reproducibility and open new prospects for a broad range of applications in the field of precision and personalized regenerative medicine.

FK506 Induces Ligand-Independent Activation of the Bone Morphogenetic Protein Pathway and Osteogenesis.

Osteoinductive bone morphogenetic proteins (BMPs), including BMP-2, have a unique capability of mediating bone formation both in orthotopic and ectopic locations. Immunosuppresive macrolides have been shown to potentiate BMP-2 activity through FKBP12, but these have yet to translate to effective osteoinductive therapies. Herein, we show the osteogenic activity of FK506 as a stand-alone agent in direct comparison to BMP-2 both in vitro and in vivo. FK506 was capable of producing stand-alone alkaline phosphatase induction in C2C12 cells comparable to that seen with rhBMP-2. FK506 treatment activated the BMP receptor, as shown by increased pSmad1/5 levels, and produced significantly higher mRNA levels of the early response genes in BMP and TGF-ß pathways. Additionally, the FK506 induction of alkaline phosphatase was shown to be resistant to Noggin treatment. In vivo osteogenic activity of FK506 was tested by local delivery on a collagen sponge in an ectopic subcutaneous implantation model in the rat. Dose responses of FK506 showed increasing levels of ectopic mineralization comparable to the mineral volume produced by BMP-2 delivery. These findings suggest that the use of FK506 can enhance osteoblastic differentiation in vitro and can induce mineralization when delivered locally in vivo.