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Rinnakkaistallenteet Luonnontieteiden ja metsätieteiden tiedekunta
2021
Nanotechnology and Osteoarthritis.
Part 1: Clinical Landscape and
Opportunities for Advanced Diagnostics
Lawson, TB
Wiley
Tieteelliset aikakauslehtiartikkelit
© 2020 Orthopaedic Research Society All rights reserved
http://dx.doi.org/10.1002/jor.24817
https://erepo.uef.fi/handle/123456789/24497
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Nanotechnology and Osteoarthritis: Clinical Landscape and Opportunities for Advanced Diagnostics
Taylor B. Lawson1,2, Janne T.A. Mӓkelӓ3, Travis Klein4, Brian D. Snyder2*, and Mark W.
Grinstaff1*
1Departments of Biomedical Engineering, Mechanical Engineering, Chemistry, and Medicine Boston University, Boston, MA 02215. 2Center for Advanced Orthopaedic Studies, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA. 3Department of Applied Physics, University of Eastern Finland, Kuopio, Finland. 4Center for Biomedical Technologies, Queensland University of Technology, Brisbane, Australia
Abstract: Osteoarthritis (OA) is a disease of the entire joint, often triggered by cartilage injury, mediated by a cascade of inflammatory pathways involving a complex interplay among
metabolic, genetic and enzymatic factors that alter the biochemical composition, microstructure and biomechanical performance. Clinically, OA is characterized by degradation of the articular cartilage, thickening of the subchondral bone, inflammation of the synovium, and degeneration of ligaments that in aggregate reduce joint function and diminish quality of life. OA is the most prevalent joint disease, affecting 140 million people worldwide; these numbers are only expected to increase, concomitant with societal and financial burden of care. We present a two-part review encompassing the applications of nanotechnology to the diagnosis and treatment of osteoarthritis (OA). Herein, Part 1 focuses on OA treatment options and advancements in nanotechnology for the diagnosis of OA and imaging of articular cartilage, while Part 2 (insert DOI) summarizes recent advances in drug delivery, tissue scaffolds, and gene therapy for the treatment of OA.
Specifically, Part 1 begins with a concise review of the clinical landscape of OA, along with current diagnosis and treatments. We next review nanoparticle contrast agents for minimally
This is the peer reviewed version of the following article: Lawson, TB, Mäkelä, JTA, Klein, T, Snyder, BD, Grinstaff, MW. Nanotechnology and osteoarthritis; part 1: Clinical landscape and opportunities for advanced diagnostics. J Orthop Res. 2020; 1– 8., which has been published in final form at https://doi.org/10.1002/jor.24817 This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions
for Use of Self-Archived Versions.
invasive detection, diagnosis, and monitoring of OA via MRI, CT, and photoacoustic imaging techniques as well as for probes for cell tracking. We conclude by identifying opportunities for nanomedicine advances, and future prospects for imaging and diagnostics.
1. NANOTECHNOLOGY
Nanotechnology is the design, manipulation, and control of materials and phenomena at atomic, molecular, and macromolecular scales. Physical, rheological, and mechanical properties as well as biological responses of materials depend on their size. At very small dimensions – i.e., nano-scale, 109 meters – materials exhibit novel properties including fluorescence, enhanced magnetism, augmented load capacity, and improved cell internalization, often the consequence of confined electronic
structure and increased surface area. Nano is not new; early examples of nanomaterials date back centuries to craftsmen who created stained glass windows and wine glasses using silicate (Egyptian Blue), as well as gold and
silver nanoparticles (Lycurgus cup).1,2 Nanotechnology is part of our daily lives, from Apple’s
“iPod Nano” to protective sunscreens. In medicine, clinically approved nano-technologies include: 1) liposome encapsulated amphotericin B (Ambisome), doxorubicin (Doxil), and irinotecan (Onivyde) for treating fungal infections, ovarian cancer, and pancreatic cancer, respectively; 2) iron nanoparticles (Ferumoxytol) for treating of iron deficiency anemia; 3) albumin coated paclitaxel nanoparticles (Abraxane) for treating metastatic breast cancer and non-small-cell lung cancer; 4) nanocrystals of Aprepitant as an antiemetic; 5) dendritic
Figure 1. Facets of nanotechnology investigated for a multitude of applications for osteoarthritis, from drug delivery to diagnosis. Part 1 of this review focuses on nanotechnology based diagnostics and imaging probes for labeling chondrocytes and synoviocytes.
polymers (Adherus) as a tissue sealant. Currently, there is no FDA approved technology for the diagnosis or treatment of osteoarthritis (OA). However, opportunities abound, and results from pre-clinical studies, described below, warrant continued efforts and translation to the clinic.
Herein Part 1, we review applications for nanotechnology within the context of evaluating and diagnosing OA (Fig. 1).
OSTEOARTHRITIS (OA)
OA is a chronic, synovial joint arthrosis afflicting 140 million people worldwide.
Associated treatments cost $125 billion annually.3 OA is progressive; changes in joint structure and function appear relatively late in the disease process, but account for long-term morbidity and disability experienced by OA patients. OA affects all synovial joint structures, including the synovium, joint capsule, cartilage, and bone. Biochemical,4 mechanical ,5 metabolic ,6,7 and genetic8 factors are etiologically related to OA. While the etiology is multi-factorial, OA is typically induced by acute or chronic mechanical injury to hyaline cartilage - the smooth, hydrated tissue that lines articular joint
surfaces (Fig. 2) - as a consequence of trauma, joint instability, ligamentous deficiency, skeletal malalignment, obesity or anatomic deformity.
Mechanical overloading results in glycosaminoglycans (GAG) loss,9 collagen disorganization,10
fibrillation,11 tissue swelling,12 and
Figure 2. Schematic of zonal differentiation within articular and a representative histological slice. Histological slice reprinted with permission.
surface wear13 and incites an inflammatory response mediated by a cascade of cytokines.
Elevated cytokines in OA synovial fluid (e.g., IL-1α, TNF-α)14 induce enzyme-mediated (e.g., metalloproteinases and ADAMTS) cartilage degeneration.15 Additionally, in OA, the synovial fluid’s capacity for both fluid and boundary lubrication decreases due to a reduction in
hyaluronic acid Mw and lubricin degradation.16 In advanced OA, synovial fluid contains minimal hyaluronic acid and lubricin, further contributing to poor lubricity and higher coefficient of friction (similar to saline). 16
Histopathologically, OA is characterized by the simultaneous presence of cartilage matrix degradation and repair including chondrocyte death, replication, and regeneration. At a cellular level, cartilage is catabolized by increased levels of cathepsins B and D, metalloproteinases, and IL-1 which result in increased water content, depleted proteoglycans, collagen, and altered binding of proteoglycans to hyaluronic acid in the synovial fluid. As OA progresses, there is an increased production of matrix-degrading enzymes and pro-inflammatory cytokines, which damage cartilage further. Loss of GAG, an early hallmark of OA, results in increased tissue porosity thus increasing hydraulic permeability, and increasing the flux of water through the porous network, with more of the internal load support to the solid collagen network. Repetitive damage to the collagen network further decreases tensile stiffness with subsequent loss of tissue.
OA is diagnosed based on clinical symptoms (e.g., pain, swelling, impaired function) and confirmed using imaging (e.g., plane radiographs, computed tomography [CT], magnetic resonance imaging [MRI]). Unfortunately imaging is biased toward visualizing late-stage OA pathoanatomy(i.e., cartilage volume loss, bone marrow edema, subchondral bone thickening, cyst formation and marginal osteophyte formation).17 The ability of hyaline cartilage for self- repair is limited, and irreversible breakdown occurs long before clinical symptoms and
radiographic signs are evident. OA diagnosed at a late stage, after micro- and macroscopic changes in tissue structure have transpired, worsens the prognosis and limits treatment options..
OA is incurable and difficult to treat. To ameliorate OA requires a comprehensive
approach: 1) correct mechanical factors that contribute to acute or chronic injury of chondrocytes and wear of hyaline cartilage; 2) abrogate the inflammatory cascade and neutralize catabolic enzymes that degrade hyaline cartilage; 3) reconstitute degraded cartilage tissue properties by augmenting constituent tissue elements or replacing end-stage chondral lesions.
OA DIAGNOSIS
The inability to identify cartilage damage early, when chondroprotective or
chondroregenerative strategies will be most effective, presents a clinical obstacle. Magnetic resonance imaging (MRI) and computed tomography (CT) are widely used to visualize musculoskeletal pathology. MRI possesses several advantages, including absence of ionizing radiation and capacity to examine the entire joint. Using semi-automated segmentation algorithms to create 3D surface representations of articular cartilage, MRI measures the
thickness, volume and surface topography of articular cartilage.18-20 Semiquantitative scales such as the Whole Organ MRI Score (WORMS)21 and the Boston-Leeds Osteoarthritis Knee Score (BLOKS)22 are used to score multiple features in affected joints. Several MRI-based techniques (T1 mapping, T2 mapping, T1ρ, Na+ mapping and dGEMRIC) provide images that reflect the GAG and collagen content of articular cartilage.23 Predicated on Donnan equilibrium theory, delayed Gadolinium-enhanced MRI of cartilage (dGEMRIC) uses gadopentetic acid (Gd2−) as a mobile anionic probe that partitions throughout the cartilage ECM in inverse proportion to the fixed negative charge density conferred by GAG.24 - 27 Since T1 relaxation time varies inversely with the concentration of Gd2− diffused throughout the cartilage matrix, mapped T1 relaxation
time directly indicates the spatial distribution and concentration of GAG distributed throughout the tissue, allowing differentiation between healthy and OA cartilage based on chemical
composition.28-30
CT provides affordable, fast, high-resolution images of bone, but since cartilage does not attenuate x-rays well, standard CT does not readily measure thickness, volume, or surface topography of articular cartilage in vivo. Intra-articular injection of an iodinated contrast agent facilitates visualization of articular surfaces. Computed arthrotomography has been used for decades to image articular surfaces comprising the hip, shoulder, knee, elbow and foot.31 CT arthrography is particularly useful for defining intra-articular pathoanatomy, providing rapid image acquisition, 2D-tomographic and 3D image reconstruction capability, excellent contrast resolution and segmentation of cartilage from bone, without the need for specialized
sequences.32,33 Similar to dGEMRIC, contrast-enhanced computed tomography (CECT), uses an anionic, iodinated contrast agent (Ioxaglate) that partitions throughout the tissue in inverse relation to local cartilage GAG content. To enhance CT based quantitative assessment of anionic tissue GAG composition, Grinstaff and Snyder developed cationic contrast agents that partition directly into the tissue in accordance to Donnan equilibrium so as to maintain electroneutrality.33-
38
Nanoparticles of iron, gold, bismuth, or tantalum of less than 100 nm in diameter are of significant interest as medical imaging contrast agents.33,39–41 Advances in the synthesis of nanoparticles are yielding various types of nanoparticles for qualitative and quantitative medical applications. Utilizations of these for cartilage imaging is still rare.42-44 Articular cartilage permeability is low, possesses a fixed negative charge, and pore size is typically less than 10 nm hindering nanoparticle diffusion. 45,46
Magnetic Resonance Imaging (MRI)
MRI contrast agents contain paramagnetic or superparamagnetic metal ions that alter intrinsic T1 or T2 relaxation times of nearby water molecules in the tissue where they accumulate. 46
Superparamagnetic iron oxide nanoparticles (SPIONs) are extensively employed as MRI contrast agents, owing to their unique physical, chemical, magnetic and biocompatibility properties. SPIO agents, regulatory approved for clinical use, include ferumoxides (Feridex in the USA, Endorem in Europe) with a particle size of 120 to 180 nm, and ferucarbotran (Resovist) with a particle size of about 60 nm.47Labens et al. report the first use of SPIONs as intra-articular MRI contrast agent for studying cartilage barrier function in a large animal model. 48 Injection of 12 nm SPIONs in matrix depleted and pristine porcine metacarpophalangeal joints followed by 1.5 T MRI pre- and post- imaging reveals an increased MRI signal in the matrix depleted porcine joints, indicating the MRI signal reflects the permeability caused by OA. Other uses for SPIONS in relation to OA are covered in a later section within this review. Yarmola et al. describe a SPION based technology (termed magnetic capture) for the determination of an OA biomarker in small volumes of synovial fluid in vitro and from a rat model of knee OA.49 Magnetic capture capitalizes on the translational force experienced by SPIONs in a high-gradient magnetic field to collected the magnetized material. A targeting molecule, in this case anti-CTXII to target the c- terminus telopeptide of type II collagen, is conjugated to the polymeric particles containing SPIONs within the core.49 The functionalized particles, after mixing with bovine synovial fluid and exposure to a magnetic field, aggregate on the magnetic probe. Intra-articular injection of the anti-CTXII particles in a rat stifle joint followed by collection with a magnetic probe reveals
detectable levels of c-terminus telopeptide of type II collagen in the 25 µL collected synovial fluid.49
Contrast-enhanced computed tomography (CECT)
Cationic contrast agents accumulate in cartilage tissue to a greater extent than neutral or anionic agents, due to favorable electrostatic interactions between the cationic contrast agent and the anionic GAGs.35,50 Freedman et al. report 5-10 nm in diameter tantalum oxide (Ta2O5) nanoparticles with neutral phosphonate, cationic ammonium, or anionic carboxylate ligands as potential CECT agents. The cationic Ta2O5 NP readily diffuse into ex vivo bovine cartilage and human index finger cartilage compared to neutral and anionic NPs. After IA administration in an in vivo mouse stifle joint, the cationic NPs penetrate the entire depth of the cartilage and enable imaging of cartilage tissue. 51
The concurrent loss of anionic GAGs and decrease in steric hindrance (due to increasing tissue porosity) induce contradictory effects on the diffusion of cationic contrast agents, reducing the diagnostic accuracy of CECT. Furthermore, demarcation of the synovial fluid-cartilage interface for measuring the thickness, volume and surface topography of contrast enhanced cartilage becomes more difficult as clear distinction of the tissue boundary diminishes with diffusion time. To overcome these shortcomings, Töyräs et al. describe the combined, simultaneous use of two or three cartilage permeable and impermeable contrast agents.52,53 Bismuth oxide nanoparticles (BINPs), being too large to diffuse into cartilage, accumulate at the cartilage surface and provide a high contrast signal,52,54 while tissue-permeable agents (anionic, neutral, and cationic small molecule iodine, neutral gadolinium) diffuse within cartilage and
provide an attenuation reflective of GAG content or porosity.52-55 CT’s capability to separate X- ray photon energy spectra allows the interrogation of multiple contrast agents (Fig. 3).
Photoacoustic imaging (PA)
Photoacoustic imaging (PA) integrates advantages of ultrasound with deep tissue penetration and optical imaging with high spatial resolution. Briefly, light energy absorbed by tissues causes a thermoelastic expansion generating ultrasound waves that are detected by a transducer. Optical absorption contrast images are obtained at penetration depths of only a few centimeters due to light scattering.
PA is particularly suited for imaging of peripheral joints such as fingers, hands, elbows, shoulders, knees, and ankles and thus of interest for diagnosing arthritis.56,57 Ishihara et al. show
Figure 3. A) Basic mechanism for simultaneous use of three cartilage permeable/impermeable contrast agents.
CA4+ is proportional to the fixed charge density conferred by proteoglycans (PGs) and uptake is high in healthy cartilage but low in degraded cartilage (b and c). In degenerated cartilage the tissue water content increases and steric hindrance decreases allowing more contrast agent molecules (both CA4+ and gadoteridol) to penetrate the tissue. Bismuth nanoparticles (average diameter of 194 nm) are too large to be able to diffuse into either, thus maintaining the contrast at the articulating surface at all diffusion time points.53 D) histology and synchron microCT slices of cartilage. Articulating surface and cracks are better visualized with the triple contrast agent owing to better contrast induced by bismuth nanoparticles (BiNPs) that, due to their size, are too large to diffuse into cartilage.53
that PA estimates the biomechanical and viscoelastic properties of tissue-engineered cartilage cultured from rabbit chondrocytes.58 Sun et al. report detection of osteoarthritis in an in vivo finger joint using three-dimensional quantitative photoacoustic tomography.59 Distal
interphalangeal (DIP) joints of female subjects, scanned in vivo, reveal differences in the absorption coefficients between healthy and osteoarthritic subjects. A homemade multispectral photoacoustic ultrasound computed tomography system, described by Liu et al., visually reconstructs the human finger joint systems including the skins, the blood vessels, the tendon, and the bone simultaneously.60
PA contrast agents absorb the energy of an optical laser and convert it to thermal
energy.61-63 Gold nanostructures ,64,65 carbon nanotubes,66 graphene-based nanomaterials among others are used for contrast enhancement.67 However examples of PA nano contrast agents for OA diagnosis are rare. Chen et al. describe an intra-articular injection of cationic charged melanin nanoparticles (MNPs) coated with poly-L-lysine (PLL) in a live mouse model.68 PLL–
MNPs exhibit roughly a two-fold stronger PA signal in a normal joint (with high GAG content) than an OA joint (with low GAG content) and importantly the PA signal intensity strongly correlates with sample GAG content (R2=0.83).
NANOPARTICLES FOR LABELING AND TARGETING CHONDROCYTES AND STEM CELLS
Nanoparticle-based labeling of chondrocytes and mesenchymal stem cells increases target specificity and enables non-invasive, long term tracking of cells once administered in vivo
through fluorescence, MRI, or CT based imaging.69 Today, quantum dots, superparamagnetic iron oxide, and gold NPs are such tracers or labels. Mesenchymal stem cells (MSCs) are multipotent cells with potential to differentiate into various tissue types, including bone and
cartilage. Quantum dots offer one solution to tracking MSCs, since they are resistant to chemical and metabolic degradation, possess long term photostability, and a narrow band emission
coupled with broadband excitation.69 Furthermore, when conjugated with an anti-mortalin antibody, quantum dots, provide a stable fluorescent signal of MSCs which were seeded in a 3D scaffold up to 26 weeks post-transplantation into an osteochondral defect.70 This provides a better understanding of the healing process after MSC implantation. NPs afford an alternate way to track MSCs. MSCs when loaded with 20 nm, 40 nm, and 60 nm citrate-stabilized and poly-L- lysine coated gold NPs, are viable, and function normally. These NPs enable long-term tracking of MSC differentiation and migration which can elucidate the MSCs role in tissue repair.71
Figure 4. TEM images representing cellular internalization of SPIONs and quantum dots for labeling and tracking chondrocytes. A) Cellular uptake and subcellular localization of magnetic nanoparticles in chondrocytes treated with 250 µg/mL magnetic nanoparticles, arrows indicate the locations of magnetic particles in the cells.114 B) Superparamagnetic iron oxide nanoparticle (SPIO)- labeled human bone marrow MSCs. Arrows indicate SPIONs in cytoplasm.104 (C-E) Mesenchymal stem cells (MSCs) labelled via internalizing quantum dots in reparative tissues, followed by the allogeneic transplantation of three‐
dimensional cartilaginous aggregates into osteochondral defects of rabbits. (C) At 4 weeks, (D) at 8 weeks, (E) higher magnification of framed area in D.71 All figures reprinted with permission.
Superparamagnetic iron oxide nanoparticles (SPIONs) are also tracers for MSCs.
Tracking transplanted stem cells longitudinally in time and space enables non-invasive
monitoring of cell delivery, bio-distribution, migration, survival, and tissue integration.72,73 To enhance target cell uptake of SPIONs to detectable levels for MRI applications, cationic compounds such as poly-L-lysine, protamine sulfate, lipofectamine, and polyethylenimine are used to produce cationic SPION complexes that electrostatically attach to the anionic cell membranes.74-76 In an ex vivo model of human osteochondral fragments, possessing a central cartilage defect, human bone marrow MSCs labelled with SPIONs accumulate in the defect target region as followed by a T2-weighted MRI.77 To minimize dose-dependent toxic effects on MSCs by the uptake of SPIONs, Markides et al. use the commercially available Nanomag, a 250-nm SPION to enhance the intracellular activity of standard cell-penetrating peptides, to track autologous mesenchymal stromal cells in an ovine osteochondral defect model.78 Van Buul et al.
employ ferumoxides complexed to protamine sulfate to label human bone marrow-derived mesenchymal stem cells (hBMSCs).79 Using T2 or T2* MRI sequences, SPION-labeled cells appear as a hypo-intensity after injected in an OA joint model, do not impair hBMSC secretion profiles, and enable accurate visualization by MRI using a porcine knee model.79
Polyethylenimine (PEI)-wrapped SPION–labeled bone marrow–derived mesenchymal stem cells , reported by Chen et al., enable stem cell identification in repaired articular cartilage in a minipig model.74 To improve uptake efficiency, Pang et al. describe surface neutral ganglioside GD2 modified SPIONs, as neutral ganglioside GD2 is highly expressed on the surface of MSCs.80
Magnetic NPs are also used to track chondrocytes in order to monitor growth,
differentiation, and regeneration in osteochondral defect repair. Labeling human derived MSCs
and chondroprogenitor cells with SPIONs does not hinder cell viability, MSC marker expression, or chondrocyte differentiation.72-74 Similarly, the SPION-labeling process does not adversely affect the phenotype or viability of chondrocytes or the production of major cartilage matrix constituents in vitro or in vivo.73, 80-82 Ferumoxytol-labeled matrix-associated stem cell implants (MASIs) show significant T2 shortening (22.2±3.2 ms vs 27.9±1.8 ms; P < .001) and no
difference in cartilage repair outcomes compared with unlabeled control MASIs (P > .05) in a porcine model, as described by Theruvath et al.83 2 weeks after implantation, ferumoxytol- labeled apoptotic MASIs show a loss of iron signal and higher T2 relaxation times compared with ferumoxytol-labeled viable MASIs (26.6±4.9 ms vs 20.8±5.3 ms; P = .001).83 Standard MRI shows incomplete cartilage defect repair of apoptotic MASIs at 24 weeks. Signal loss at 2 weeks correlates with incomplete cartilage repair, diagnosed at histopathologic examination at 12-24 weeks.83 Chen et al. describe an ultrasmall superparamagnetic iron oxide (USPIO)-labeled cellulose nanocrystal (CNC)/silk fibroin (SF)-blended hydrogel system for noninvasive
visualization and semiquantitative analysis of hydrogel degradation and cartilage regeneration in vitro and in rabbit cartilage regeneration in vivo.84 The USPIO-labeled hydrogel system allows for in vivo MRI detection of hydrogel absorption and neo-tissue replacement, confirmed via conventional Hematoxylin-eosin and Prussian blue staining.84
Zare et al. report a novel scaffold-free complex microtissue of chondrogenic and osteogenic cell sheets using magnetically labelled dental pulp stem cells.85 A magnetic force organizes the dental pulp stem cells, which have internalized Fe3O4 magnetic nanoparticles, to form a multilayered osteochondral complex after being seeded onto a graphene oxide sheet.85 Following implantation into nude mice, the stem cells differentiate into chondrocytes and
osteoblasts.85 Su et al. further explore this strategy using iron-oxide based magnetic nanoparticles
to both label and track chondrocytes and homogenously incorporate chondrocytes onto biphasic scaffolds. Results indicate chondrocytes successfully incorporate the magnetic nanoparticles, reaching roughly 95% incorporation when the concentration of magnetic nanoparticles is greater than 250 µg/mL.86 Further, labeled chondrocytes, when seeded into the biphasic scaffold under a one Tesla magnetic field for 60 minutes, migrate and distribute more evenly between both layers, compared to the untreated group (i.e., no magnetic field).86
CONCLUSIONS AND PERSPECTIVES
Nanotechnology offers significant potential to enhance current OA management through new diagnostic capabilities. As discussed above a number of new technologies and materials are in pre-clinical development to address this multifactorial disease. With regards to the diagnostic front, nanoparticle contrast agents for use in MRI, CT, and PA afford additional qualitative and quantitative information on cartilage structure and lesions as well as GAG content and its spatial distribution within cartilage – a known biomarker for early OA.
Although the application of nanotechnology in orthopaedics is still in its infancy, several new research opportunities exists to include 1) MRI and CT contrast agents that provide
quantitative assessment of a tissue component other than GAG; 2) functional MRI or CT agents that provide information on the biochemical or metabolic state of the tissue; 3) nanotracers for specific cells types; and, 4) theranostics, which act simultaneously as a diagnostic agent and a therapy.
The purpose of this review is to highlight the many recent advances in nanotechnology for imaging and diagnostic applications in OA, and to share our enthusiasm for this area. Part 2 of this review (Nanotechnology and Osteoarthritis: Opportunities for Advanced Devices and Therapeutics; insert DOI) expounds upon nanoparticle drug delivery systems to enable selective,
targeted delivery of disease modifying OA drugs, nanoparticle gene delivery systems, nano- based scaffolds for tissue repair, and novel nanoparticle lubricants for viscosupplementation.
Acknowledgments
The authors acknowledge funding in part from the National institutes of Health (NIH;
R01AR066621 M.W.G. and B.D.S; F31 AR075386 T.B.L.) as well as Boston University. J.T.A.M.
acknowledges funding from Instrumentarium Science Foundation and University of Eastern Finland.
Conflict of interest statement
MWG and BDS are co-inventors on a patent filed in the United States Patent and Trademark Office on the application of cationic agents for CECT imaging.
Author Contributions
Manuscript was written by all authors.
ORCID
Taylor B. Lawson 0000-0002-4674-545X
Janne T.A. Mӓkelӓ 0000-0002-6123-1262 Travis Klein
Brian D. Snyder
Mark W. Grinstaff 0000-0002-5453-3668
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