Injectable nanofiber microspheres modified with metal phenolic networks for effective osteoarthritis treatment

Osteoarthritis (OA), a chronic disease caused by the inflammation of joints, poses severe health concerns as well as discomfort worldwide [1,2]. While not being fatal, the inflammatory mediators produced by the OA may induce the degeneration of different types of tissues and organs of the musculoskeletal system, such as synovium, bone, and cartilage if not appropriately intervened [3]. Current therapeutic treatments of OA involve surgical intervention, symptom control, delivery of oral analgesics and anti-inflammatory drugs, as well as non-pharmacological treatments (e.g. self-management, advice to lose weight, etc.) [4]. While these therapeutic modalities achieve pain relief, most of them have not been proven to prevent or even slow down the progression of the disease. Therefore, it is imperative to develop safe and effective approaches to attenuate or halt the disease progression, or even reverse the disease through regeneration of new articular cartilage.

Microspheres are at the forefront of drug delivery and tissue engineering applications, displaying functions comparable to 3D scaffolds, which have already been harnessed for cell transplantation or drug/growth factor delivery at injury sites [5]. Microspheres can be injected into irregular defects or injured tissues in a minimally invasive procedure, thereby shortening the recovery time for up to several folds than that of the traditional surgical procedures as required for 3D scaffolds [6]. So far, microspheres displaying different types of shapes and structures, such as solid, hollow, and nanofibrous have been successfully fabricated. Of these, nanofiber microspheres exhibit large specific surface area, which endows them with high cell/drug loading efficiency. Ma et al. leveraged self-assembling star-shaped poly(l-lactic acid) (SS-PLA)-based nanofibrous microspheres for osteochondral repair [7]. Similarly, chitosan nanofiber microspheres were fabricated by using microfluidic device through physical gelation and exploited for the transplantation of chondrocytes for cartilage tissue engineering (CTE) [8]. Nonetheless, these platforms require the specific surface functional groups of materials, which may however be applicable to only a few polymers.

Recently, electrospinning combined with electrospraying technology has been leveraged for the production of nanofiber microspheres. This approach exploits homogenized electrospun nanofibers as raw ingredients, thereby avoiding the dense structure of the traditional electrospun nanofibers. The microstructure of nanofiber microspheres can be tailored by controlling different types of electrospraying parameters, such as applied voltage, flow rate, and spinneret-to-collector distance [9]. Besides, a series of materials, including both natural or synthetic polymers as well as inorganic oxides can be tailored into nanofiber microspheres [10,11]. Moreover, nanofiber microspheres not only display geometric compatibility, but may also be exploited for drug release due to their high specific surface area [12]. Nonetheless, the long-term mechanical stability of nanofiber microspheres requires further improvement. In addition, nanofibrous microspheres are needed to be further tailored for anti-oxidative properties, extracellular matrix (ECM) secretion, and chondrocytes protection to better satisfy the requirements for the OA treatment.

Polyphenols have been shown to exert anti-oxidative effect, which may not only neutralize harmful free radicals but also reduce cell apoptosis [13]. Tannic acid (TA) exhibits multiple pyrogallol hydroxyl groups, which afford reversible interactions with different types of the proteins, including gelatin and elastin through forming hydrogen bonds [14,15]. Besides, the adjacent hydroxyl groups in TA provide chelating sites that can be further reacted with different types of metal ions to afford 3D stable metal phenolic networks (MPNs) [16]. Moreover, TA exhibits high scavenging capacity for hydrogen peroxide (H2O2) and hydroxyl radicals (OH‧) and promotes the release of glycosaminoglycans (GAGs) against collagenase digestion. Therefore, the TA exhibits beneficial effects in protecting cartilage under OA conditions [17,18]. Strontium (Sr), an important trace element in the human body, has been widely used for the treatment of osteoporosis and has been shown to have a positive intervention on cartilage matrix remodeling [19], [20], [21]. Given the studies above, we hypothesized that the construction of strontium and TA mediated MPNs on nanofiber microspheres may enhance the bioactivity of microspheres and achieve the synergistic effect of antioxidant and chondrocyte anabolism to meet the requirements for OA therapy.

The objective of this study is therefore to design MPNs modified electrospray nanofiber microspheres and to evaluate their potential for OA treatment for the first time. Herein, we prepared gelatin/poly(L-lactide) (gelatin/PLA)-based nanofiber microspheres by electrospraying the aqueous dispersions of electrospun homogenized short fibers. The nanofiber microspheres were further modified with TA or TA/Sr2+ MPNs and were intensively characterized for morphological and physico-chemical characteristics, anti-oxidative ability, and drug/ion release. In addition, nanofiber microspheres were investigated in terms of anti-apoptosis, resolution of inflammatory cytokines as well as the secretion of cartilage-related ECM both in vitro and in vivo in an OA environment.

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