Controlled dual drug release from adhesive electrospun patches for prevention and treatment of alveolar osteitis

Abstract

Approximately one in five individuals experience alveolar osteitis (AO) following wisdom tooth extraction. AO is characterised by loss of the blood clot from the tooth extraction socket leading to infection and pain, resulting in repeated hospital visits that impose a substantial burden on healthcare systems. Current treatments are sub-optimal; to address this we developed a novel drug-loaded mucoadhesive patch composed of dual electrospun polyvinyl pyrrolidone/Eudragit RS100 (PVP/RS100) and poly(N-isopropylacrylamide) (PNIPAM) fibres protected by a poly(ε-caprolactone) (PCL) backing layer. These patches demonstrated controlled release of the long-acting analgesic bupivacaine HCl and the anti-inflammatory drug prednisolone. Topical application of patches to tissue-engineered gingival mucosa showed that patch-released bupivacaine and prednisolone achieved sustained tissue permeation with 54.8 ± 3.3 % bupivacaine HCl and 65.8 ± 5.1 % prednisolone permeating the epithelium after 24 h. The drugs retained their functionality after release; bupivacaine HCl significantly (p < 0.05) inhibited veratridine-induced intracellular calcium flux in SH-SY5Y neuronal cells, while prednisolone significantly reduced gene expression of IL-6 (2-fold; p < 0.001), CXCL8 (5.1-fold; p < 0.01) and TNF-α (1.5-fold; p < 0.001) in stimulated THP-1 monocytes. Taken together, these data show that dual electrospun patches have the potential to provide a mucoadhesive covering to prevent blood clot loss while delivering pain relief and anti-inflammatory therapeutics at tooth extraction sites to prevent and treat AO. This study not only offers a future therapeutic pathway for AO but also contributes valuable insights into future advancements in drug delivery devices for periodontal or oral mucosal tissue.

Highlights

• Mucoadhesive electrospun patch that simultaneously delivers pain relief and anti-inflammatory drugs.
• Dual electrospun PVP/RS100 and PNIPAM microfibres achieve controlled drug release.
• Patches reduce cytokine secretion in a 3D in vitro model of gingival inflammation.
• Patch treatment blocks cell voltage-gated sodium channels for pain relief.

Introduction

Alveolar osteitis (AO), commonly referred to as ‘dry socket’ poses a significant challenge in dental practice, often complicating tooth extraction procedures. The condition arises when the blood clot that forms in the tooth socket post-extraction becomes dislodged or disintegrates prematurely, exposing the underlying alveolar bone [1]. This exposure leads to acute and persistent pain and inflammation that prolongs the healing process, causing distress to patients [2]. Tooth extractions are the among the most common surgeries. For example, over 3.3 million of these procedures were performed in England in 2022–23 [3], while in the US around 10 million third molar (wisdom) tooth extractions are performed annually [4]. The reported incidence of AO is up to 5 % of all routine extractions but this increases to 30 % for wisdom tooth extractions [5]. Therefore, AO is a considerable clinical problem.Although the precise aetiology remains elusive, several risk factors such as smoking [6], age, gender [7], oestrogen levels [8] and oral health [9] are all known to have an impact. The incidence of AO is most common in the lower third molar teeth due to denser alveolar bone, which is associated with reduced vascularisation [1].

Current clinical guidelines for the management of AO recommend irrigation of the post-extraction tooth socket to remove debris and necrotic tissue without blood clot dislodgement, followed by the application of an intra-socket dressing such as Alveogyl or zinc oxide eugenol (ZOE) for temporary pain relief, with longer term pain management typically involving a combination of analgesics, such as paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs) [10]. SaliCept, a freeze-dried pledget containing an acemannan hydrogel derived from aloe vera that is applied intra-socket, has also been found to reduce incidence of AO [11]. However, the efficacy of these interventions is limited, and patients may require multiple visits for irrigation and dressing changes as the socket heals. Moreover, Alvogyl and ZOE contain eugenol that has been reported to cause hypersensitivity reactions as well as bone necrosis that may delay healing of the extraction socket [2,12]. Treatment with platelet-rich fibrin or low-level laser therapy offer promising alternatives in reducing AO and improving healing outcomes [13,14]. However, conflicting evidence and variability in study findings underscore the need for further research to establish their efficacy [15,16].Antibiotics were previously advocated for AO prevention but there is a lack of robust evidence to support their routine use, especially given the increasing risk of antimicrobial resistance [17,18]. Chlorhexidine mouthwash, a commonly used antiseptic, has shown some efficacy in reducing AO incidence [19].

Prevention strategies aimed at mitigating the risk of clot dislodgement to promote optimal healing would be highly beneficial. To this end, the utilisation of a protective membrane to cover the post-extraction socket has shown promising outcomes.Oxidised cellulose membranes have proved effective by stabilising the blood clot within the socket [20]. While, collagen membranes have shown to support wound healing by stabilising clots and possessing haemostatic properties [21]. A disadvantage of these systems is that they require suturing which is technically demanding and extends clinical time making it more expensive.Recently, we have developed an electrospun mucoadhesive patch for targeted delivery of the anti-inflammatory corticosteroid, clobetasol-17-propionate, for the treatment of inflammatory oral mucosal diseases [22,23] and lidocaine for pain management [24]. The patch formulation utilises polyvinyl pyrrolidone (PVP)/Eudragit RS100 (RS100) as drug-loaded, fibre-forming polymers that demonstrate rapid drug release profiles [25]. The patch also comprises a hydrophobic backing layer of poly(ε-caprolactone) (PCL) to protect the mucoadhesive layer against mechanical forces, saliva and to ensure unidirectional delivery of drugs into the mucosa [23].

These microfibre patches are fabricated using electrospinning technology, where monoaxial electrospinning, the production of a homogeneous fibre patch from a single polymer mixture, is most common. However, incorporation of heterogeneous polymers fibres into a patch can be achieved using coaxial, triaxial, side-by-side/Janus or multi-jet techniques [26,27,28].Inclusion of additional polymers in the fabrication process offers tailorability for longer-term adhesion with sustained release properties. Poly(N-isopropylacrylamide) (PNIPAM) is a thermoresponsive polymer with excellent electrospinning qualities [29,30] that has gained attention for controlled drug release [31]. PNIPAM is water soluble below its lower critical solution temperature of approximately 32 °C [32]. However, at physiological temperatures close to 37 °C electrospun PNIPAM forms a relatively hydrophobic hydrogel that is suitable for efficient and sustained drug release over several hours [33,34]. Electrospun technologies clearly have wider potential applications in oral medicine and dentistry, including in the development of new sustained drug delivery devices for treatment of AO as predicted by Edmans et al [35].

Herein, we successfully incorporated bupivacaine HCl, tramadol HCl (analgesics), celecoxib, naproxen (COX-2 inhibitor; NSAID) or prednisolone (corticosteroid) into PVP/RS100 electrospun mucoadhesive patches. These patches demonstrated rapid release of prednisolone and bupivacaine HCl. To control drug release, prednisolone-loaded PVP/RS100 fibres were electrospun in conjunction with bupivacaine HCl-loaded PNIPAM polymer fibres. In the dual electrospun patch, PNIPAM fibres produced sustained release of bupivacaine while simultaneously inducing controlled release of prednisolone from the PVP/RS100 fibres, without affecting patch adhesion. The drugs released from the dual electrospun patch permeated human tissue engineered gingival mucosal equivalents and retained their anaesthetic activity while suppressing a leukocyte-mediated inflammatory response. These patches will deliver both anti-inflammatory and anaesthetic therapeutics directly to the post-extraction site in a controlled manner whilst simultaneously retaining the blood clot in place, signifying a potential step-change in the prevention and treatment of AO.

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Materials

All reagents were purchased from Merck (Gillingham, UK) unless otherwise stated. PVP (MW 2000 kDa) and RS100 (MW 38 kDa) were kindly donated by BASF (Cheadle Hulme, UK) and Evonik Industries AG (Essen, Germany), respectively.

Klaudia M. Slowik, Jake G. Edmans, Samuel Harrison, Sean M. Edwards, Robert Bolt, Sebastian G. Spain, Paul V. Hatton, Craig Murdoch, Helen E. Colley, Controlled dual drug release from adhesive electrospun patches for prevention and treatment of alveolar osteitis, Journal of Controlled Release, Volume 376, 2024, Pages 253-265, ISSN 0168-3659, https://doi.org/10.1016/j.jconrel.2024.09.048.

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