Dynamic Release from Acetalated Dextran Nanoparticles for Precision Therapy of Inflammation.

Polymer-based nanoparticles (NPs) that react to altered physiological characteristics have the potential to enhance the delivery of therapeutics to a specific area. These materials can utilize biochemical triggers, such as low pH, which is prone to happen locally in an inflammatory microenvironment due to increased cellular activity. This reduced pH is neutralized when inflammation subsides. For precise delivery of therapeutics to match this dynamic reaction, drug delivery systems (DDS) need to not only release the drug (ON) but also stop the release (OFF) autonomously. In this study, we use a systematic approach to optimize the composition of acetalated dextran (AcDex) NPs to start (ON) and stop (OFF) releasing model cargo, depending on local pH changes. By mixing ratios of AcDex polymers (mixed NPs), we achieved a highly sensitive material that was able to rapidly release cargo when going from pH 7.4 to pH 6.0. At the same time, the mix also offered a stable composition that enabled a rapid ON/OFF/ON/OFF switching within this narrow pH range in only 90 min. These mixed NPs were also sensitive to biological pH changes, with increased release in the presence of inflammatory cells compared to healthy cells. Such precise and controllable characteristics of a DDS position mixed NPs as a potential treatment platform to inhibit disease flare-ups, reducing both systemic and local side effects to offer a superior treatment option for inflammation compared to conventional systems.

Achieving Precision Healthcare through Nanomedicine and Enhanced Model Systems.

The ability to customize medical choices according to an individual's genetic makeup and biomarker patterns marks a significant advancement toward overall improved healthcare for both individuals and society at large. By transitioning from the conventional one-size-fits-all approach to tailored treatments that can account for predispositions of different patient populations, nanomedicines can be customized to target the specific molecular underpinnings of a patient's disease, thus mitigating the risk of collateral damage. However, for these systems to reach their full potential, our understanding of how nano-based therapeutics behave within the intricate human body is necessary. Effective drug administration to the targeted organ or pathological niche is dictated by properties such as nanocarrier (NC) size, shape, and targeting abilities, where understanding how NCs change their properties when they encounter biomolecules and phenomena such as shear stress in flow remains a major challenge. This Review specifically focuses on vessel-on-a-chip technology that can provide increased understanding of NC behavior in blood and summarizes the specialized environment of the joint to showcase advanced tissue models as approaches to address translational challenges. Compared to conventional cell studies or animal models, these advanced models can integrate patient material for full customization. Combining such models with nanomedicine can contribute to making personalized medicine achievable.

Physiological levels of estradiol limit murine osteoarthritis progression.

Among patients with knee osteoarthritis (OA), postmenopausal women are over-represented. The purpose of this study was to determine whether deficiency of female sex steroids affects OA progression and to evaluate the protective effect of treatment with a physiological dose of 17ß-estradiol (E2) on OA progression using a murine model. Ovariectomy (OVX) of female mice was used to mimic a postmenopausal state. OVX or sham-operated mice underwent surgery for destabilization of the medial meniscus (DMM) to induce OA. E2 was administered in a pulsed manner for 2 and 8 weeks. OVX of OA mice did not influence the cartilage phenotype or synovial thickness, while both cortical and trabecular subchondral bone mineral density (BMD) decreased after OVX compared with sham-operated mice at 8 weeks post-DMM surgery. Additionally, OVX mice displayed decreased motor activity, reduced threshold of pain sensitivity, and increased number of T cells in the inguinal lymph nodes compared to sham-operated mice 2 weeks after OA induction. Eight weeks of treatment with E2 prevented cartilage damage and thickening of the synovium in OVX OA mice. The motor activity was improved after E2 replacement at the 2 weeks time point, which was also associated with lower pain sensitivity in the OA paw. E2 treatment protected against OVX-induced loss of subchondral trabecular bone. The number of T cells in the inguinal lymph nodes was reduced by E2 treatment after 8 weeks. This study demonstrates that treatment with a physiological dose of E2 exerts a protective role by reducing OA symptoms.

Biomaterial Integration in the Joint: Pathological Considerations, Immunomodulation, and the Extracellular Matrix.

Defects of articular joints are becoming an increasing societal burden due to a persistent increase in obesity and aging. For some patients suffering from cartilage erosion, joint replacement is the final option to regain proper motion and limit pain. Extensive research has been undertaken to identify novel strategies enabling earlier intervention to promote regeneration and cartilage healing. With the introduction of decellularized extracellular matrix (dECM), researchers have tapped into the potential for increased tissue regeneration by designing biomaterials with inherent biochemical and immunomodulatory signals. Compared to conventional and synthetic materials, dECM-based materials invoke a reduced foreign body response. It is therefore highly beneficial to understand the interplay of how these native tissue-based materials initiate a favorable remodeling process by the immune system. Yet, such an understanding also demands increasing considerations of the pathological environment and remodeling processes, especially for materials designed for early disease intervention. This knowledge will avoid rejection and help predict complications in conditions with inflammatory components such as arthritides. This review outlines general issues facing biomaterial integration and emphasizes the importance of tissue-derived macromolecular components in regulating essential homeostatic, immunological, and pathological processes to increase biomaterial integration for patients suffering from joint degenerative diseases.