Osteoarthritis (OA) is a degenerative disease of the joints and a leading cause of physical disability in adults. Intra‐articular (IA) therapy is a popular treatment strategy for localized, single‐joint OA; however, small‐molecule drugs such as corticosteroids do not provide prolonged relief. One possible reason for their lack of efficacy is high clearance rates from the joint through constant lymphatic drainage of the synovial tissues and synovial fluid and also by their exchange via the synovial vasculature. Advanced drug delivery strategies for extended release of therapeutic agents in the joint space is a promising approach to improve outcomes for OA patients. Broadly, the basic principle behind this strategy is to encapsulate therapeutic agents in a polymeric drug delivery system (DDS) for diffusion‐ and/or degradation‐controlled release, whereby degradation can occur by hydrolysis or tied to relevant microenvironmental cues such as pH, reactive oxygen species (ROS), and protease activity. In this review, the development of clinically tested IA therapies for OA and recent systems which have been investigated preclinically are highlighted. DDS strategies including hydrogels, liposomes, polymeric microparticles (MPs) and nanoparticles (NPs), drug conjugates, and combination systems are introduced and evaluated for clinical translational potential.

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Exogenous electrical stimulation (ES) has been investigated as a therapy for chronic wounds, as the skin produces currents and electrical fields (EFs) during wound healing. ES therapies operate by applying small EFs to the skin to mimic the transepithelial potentials that occur during the granulation phase of wound healing. Here, we investigated the effect of short duration (10 min) ES on the migration of HDFs using various magnitudes of physiologically relevant EFs. We modeled cutaneous injury by culturing HDFs in custom chambers that allowed the application of ES and then performed timelapse microscopy on a standard wound model. Using MATLAB to process cell coordinate data, we determined that the cells were migrating randomly and fit mean squared displacement data to the persistent random walk equation using nonlinear least squares regression analysis. Results indicated that application of 25-100 mV/mm DC EFs to HDFs on either uncoated or FN-coated surfaces demonstrated no significant changes in viability or proliferation. Of significance is that the HDFs increased random migration behavior under some ES conditions even after 10 min, providing a mechanism to enhance wound healing.

Porous, resorbable biomaterials can serve as temporary scaffolds that support cell infiltration, tissue formation, and remodeling of nonhealing skin wounds. Synthetic biomaterials are less expensive to manufacture than biologic dressings and can achieve a broader range of physiochemical properties, but opportunities remain to tailor these materials for ideal host immune and regenerative responses. Polyesters are a well-established class of synthetic biomaterials; however, acidic degradation products released by their hydrolysis can cause poorly controlled autocatalytic degradation. Here, we systemically explored reactive oxygen species (ROS)–degradable polythioketal (PTK) urethane (UR) foams with varied hydrophilicity for skin wound healing. The most hydrophilic PTK-UR variant, with seven ethylene glycol (EG7) repeats flanking each side of a thioketal bond, exhibited the highest ROS reactivity and promoted optimal tissue infiltration, extracellular matrix (ECM) deposition, and reepithelialization in porcine skin wounds. EG7 induced lower foreign body response, greater recruitment of regenerative immune cell populations, and resolution of type 1 inflammation compared to more hydrophobic PTK-UR scaffolds. Porcine wounds treated with EG7 PTK-UR foams had greater ECM production, vascularization, and resolution of proinflammatory immune cells compared to polyester UR foam–based NovoSorb Biodegradable Temporizing Matrix (BTM)–treated wounds and greater early vascular perfusion and similar wound resurfacing relative to clinical gold standard Integra Bilayer Wound Matrix (BWM). In a porcine ischemic flap excisional wound model, EG7 PTK-UR treatment led to higher wound healing scores driven by lower inflammation and higher reepithelialization compared to NovoSorb BTM. PTK-UR foams warrant further investigation as synthetic biomaterials for wound healing applications.

Oxidative stress is broadly implicated in chronic, inflammatory diseases because it causes protein and lipid damage, cell death, and stimulation of inflammatory signaling. Supplementation of innate antioxidant mechanisms with drugs such as the superoxide dismutase (SOD) mimetic compound 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) is a promising strategy for reducing oxidative stress-driven pathologies. TEMPO is inexpensive to produce and has strong antioxidant activity, but it is limited as a drug due to rapid clearance from the body. It is also challenging to encapsulate into micellar nanoparticles or polymer microparticles, because it is a small, water soluble molecule that does not efficiently load into hydrophobic carrier systems. In this work, we pursued a polymeric form of TEMPO [poly(TEMPO)] to increase its molecular weight with the goal of improving in vivo bioavailability. High density of TEMPO on the poly(TEMPO) backbone limited water solubility and bioactivity of the product, a challenge that was overcome by tuning the density of TEMPO in the polymer by copolymerization with the hydrophilic monomer dimethylacrylamide (DMA). Using this strategy, we formed a series of poly(DMA-co-TEMPO) random copolymers. An optimal composition of 40 mol % TEMPO/60 mol % DMA was identified for water solubility and O 2•− scavenging in vitro. In an air pouch model of acute local inflammation, the optimized copolymer outperformed both the free drug and a 100% poly(TEMPO) formulation in O 2•− scavenging, retention, and reduction of TNFα levels. Additionally, the optimized copolymer reduced ROS levels after systemic injection in a footpad model of inflammation. These results demonstrate the benefit of polymerizing TEMPO for in vivo efficacy and could lead to a useful antioxidant polymer formulation for next-generation anti-inflammatory treatments.