Elsevier

Journal of Controlled Release

Volume 268, 28 December 2017, Pages 237-246
Journal of Controlled Release

Transfer-molded wrappable microneedle meshes for perivascular drug delivery

https://doi.org/10.1016/j.jconrel.2017.10.007Get rights and content

Abstract

After surgical procedures such as coronary/peripheral bypass grafting or endarterectomy for the treatment of organ ischemia derived from atherosclerosis, intimal hyperplasia (IH) which leads to restenosis or occlusion at the site of graft anastomosis frequently occurs. In order to inhibit IH caused by abnormal growth of smooth muscle cells (SMCs) in tunica media, various perivascular drug delivery devices are reported for delivery of anti-proliferation drugs into vascular tissue. However, there still remain conflicting requirements such as local and unidirectional delivery vs device porosity, and conformal tight device installation vs pulsatile expansion and constriction of blood vessels. In this study, a biodegradable microneedle (MN) array is developed on a flexible woven surgical mesh using a transfer molding method. Mechanical properties of ‘wrappable’ MN meshes are investigated and compared to the properties of blood vessels. Ex vivo and in vivo animal studies demonstrate enhanced drug delivery efficiency, efficacy for IH reduction, and safety of MN mesh. In particular, MN mesh showed significantly reduced neointiamal formation (11.1%) compared to other competitive groups (23.7 and 22.2%) after 4-week in vivo animal study. Additionally, wrappable MN meshes effectively suppressed side effects such as IH due to mechanical constriction, loss of toxic drug to the surroundings, and cell death that were frequently observed with other previous perivascular drug delivery devices.

Introduction

Intimal hyperplasia (IH) occurs at the site of anastomosis and leads to stenosis or occlusion of vascular grafting sites of coronary or peripheral bypass grafting [1], endarterectomy [2], or arteriovascular (AV) grafting for dialysis [3], [4]. Wound damage to vascular tissue during such vascular surgery causes IH due to abnormal growth of smooth muscle cells (SMCs) from tunica media or migration of myofibroblasts from the perivascular layers. IH can be suppressed using well-known anti-proliferative drugs such as paclitaxel [5], [6] and sirolimus [7], [8], [9].

A great number of technologies for vascular drug delivery have been reported including drug eluting stents (DES) [10], [11], [12], and drug eluting balloons (DEB) [13], [14]. However, these technologies are only suitable for drug delivery from the inside of blood vessels, and not applicable to the IH occurring from open vascular surgeries. In recent studies, different forms of devices such as films/wraps [15], [16], [17], [18], [19], depot gels [20], [21], meshes [22], [23], [24], rings [25], or micro/nano particles [26], [27] were reported for perivascular delivery of anti-proliferation compounds. These studies demonstrated the feasibility of delivering drugs to vascular tissue and enhanced efficacy in reducing IH in animal studies.

To further develop perivascular drug delivery (PDD) devices for clinical trials, however, there still remain multiple challenges such as control of release rates, matching of mechanical property, effect of biodegradation, and side effects of delivered drug to surrounding tissue. Overdose can be toxic to blood vessels, while low dose results in no efficacy. Mechanical stresses due to the application of PDD devices on blood vessels may cause unwanted proliferation of smooth muscle cells in the vessels [28], [29]. Long-term presence of PDD devices over blood vessels without biodegradation, or loss of drug to the surrounding tissue also poses potential problems. Lack of proper installation of PDD devices without secure conformal contact on blood vessels (e.g. film or mesh type devices) can also cause loss of drug and unpredicted outcomes.

Microneedle (MN) technology has been highlighted as an outstanding drug delivery method across tissue barriers [30], [31]. For more localized and highly efficient delivery of anti-proliferative drug to vascular tissue suffering from IH, we previously proposed a PDD device that contained an array of MNs within the internal surface of cylindrical cuffs [32], [33], [34], [35]. It was designed to make full penetration of MNs through tunica adventitia with slight insertion or contact to tunica media. After installation of the MN cuff over a blood vessel, paclitaxel (PTX), an anti-proliferative drug, was released from the MN tips such that drug delivery was highly localized only to the vascular tissue. Both localized delivery of PTX and enhanced efficacy of reducing IH were confirmed using MN cuff devices. However, in animal studies, vascular tissue was deformed where the MN cuffs were applied. This indicated constrictive mechanical stress to vascular tissue due to the rigidity of the MN cuffs.

There are previous studies that developed MNs on flexible substrates made of elastomeric materials such as PDMS [36], parylene [37], PEG [38], or PVP [39]. However, they are merely bendable with limited curvatures [40] or too thick to be wrapped around blood vessels [41]. In addition, most of them are solid substrates that can damage blood vessels by blocking their molecule exchange with surrounding environments. Although a MN-shaped electrode mesh was reported recently [42], the thin, non-degradable substrate is unsuitable for wrapping blood vessels and long-term implantation.

In this study, we propose “wrappable” MN mesh devices that can wrap around blood vessels and conform to the exterior surface of the vessels (Fig. 1). A biodegradable surgical mesh was employed as a wrappable substrate to minimize mechanical stress to blood vessels as well as to provide adequate molecular exchange of vascular tissue through the mesh after installation. In order to fabricate MNs on rough and fibrous woven meshes, a transfer molding technique was developed. Transfer molding allowed for MN fabrication at localized spots of a mesh substrate without affecting the mechanical property of the meshes. Modulus matching of MN mesh devices as well as stability of MN adhesion during stretch tests was characterized by uniaxial stretch testing. Ex vivo and in vivo studies were performed to confirm MN insertion to vascular tissue and localized drug delivery in vascular tissue. Finally, reduction of IH with minimal tissue deformation, vascular integrity with MN meshes, and proliferative activity of SMCs were demonstrated, using a rabbit aorta balloon injury model.

Section snippets

Materials

Biodegradable poly(lactic-co-glycolic acid) (PLGA) 90/10 meshes (Neosorb® meshes) and PLGA80/20 were generously donated by Samyang Biopharm Corp., Republic of Korea. Polydimethylsiloxane (PDMS) (Sylgard® 184 silicone elastomer kit) was purchased from Dow Corning, MI, U.S.A. and used at a mixing ratio of 10:1 (silicone elastomeric base: curing agent, weight ratio) to fabricate negative molds for transfer molding. PLGA50/50 (B6013-1, Lactel, AL, U.S.A.), dimethyl sulfoxide (DMSO) (D0457, Samchun

Transfer molding of MNs on surgical mesh

To fabricate an array of MNs on the surface of a flexible and porously woven mesh, transfer molding was used. Arrays of PLGA80/20 MNs with heights of 480, 640, and 780 μm were fabricated on PLGA90/10 meshes in precise accordance with the sizes of the MN cavities of PDMS molds (Fig. 2 and S3). For sufficient melting of polymer, PLGA80/20 pellets were heated up to 200 °C, which is above the glass transition temperature of PLGA80/20. When a stainless micro-pillar heated up to 160 °C contacted the

Discussion

Perivascular “wrappable” MN mesh devices were fabricated to deliver anti-proliferative drug into injured blood vessels for reduction of intimal hyperplasia with reduced mechanical stress by MN devices to vascular tissue. Although there have been previous studies of MNs on flexible substrates [37], [42], [49], [50], they were fabricated by lithography and chemical deposition methods, which are incompatible with fiber mesh structures or biodegradable polymers. For perivascular drug delivery, a

Conclusion

In this work, we developed a wrappable MN mesh to deliver anti-proliferative drug into injured blood vessels for IH reduction with minimal mechanical stress. An array of MNs was constructed on the surface of fibrous surgical meshes using transfer molding. Mechanical characterization confirmed suitability of the surgical mesh as wrappable substrates for minimization of mechanical stresses applied to blood vessels as well as stability of MN adhesion. Animal studies using MN meshes demonstrated

Conflict of interest

None.

Acknowledgements

This work was supported by the National Research Foundation of Korea (NRF) Grant funded by the Korean Government (MSIT) (No. 2015R1A5A1037668). The authors specially thank Samyang Biopharmaceuticals for generous donation of PLGA90/10 meshes and PLGA80/20 pellets.

References (56)

  • Y.-C. Kim et al.

    Microneedles for drug and vaccine delivery

    Adv. Drug Deliv. Rev.

    (2012)
  • C.K. Choi et al.

    Spatially discrete thermal drawing of biodegradable microneedles for vascular drug delivery

    Eur. J. Pharm. Biopharm.

    (2013)
  • K.J. Lee et al.

    Perivascular biodegradable microneedle cuff for reduction of neointima formation after vascular injury

    J. Control. Release

    (2014)
  • B. Cai et al.

    Bioceramic microneedles with flexible and self-swelling substrate

    Eur. J. Pharm. Biopharm.

    (2015)
  • A. Duprey et al.

    In vitro characterisation of physiological and maximum elastic modulus of ascending thoracic aortic aneurysms using uniaxial tensile testing

    Eur. J. Vasc. Endovasc. Surg.

    (2010)
  • D. Wiedemann et al.

    Perivascular administration of drugs and genes as a means of reducing vein graft failure

    Curr. Opin. Pharmacol.

    (2012)
  • M.A. Chaudhary et al.

    Periadventitial drug delivery for the prevention of intimal hyperplasia following open surgery

    J. Control. Release

    (2016)
  • O. Jeon et al.

    Affinity-based growth factor delivery using biodegradable, photocrosslinked heparin-alginate hydrogels

    J. Control. Release

    (2011)
  • M.F. Fillinger et al.

    Beneficial effects of banding on venous intimal-medial hyperplasia in arteriovenous loop grafts

    Am. J. Surg.

    (1989)
  • M.W. Liu et al.

    Restenosis after coronary angioplasty. Potential biologic determinants and role of intimal hyperplasia

    Circulation

    (1989)
  • T.C. Rothuizen et al.

    Arteriovenous access failure: more than just intimal hyperplasia?

    Nephrol. Dial. Transplant.

    (2013)
  • A.W. Heldman et al.

    Paclitaxel stent coating inhibits neointimal hyperplasia at 4 weeks in a porcine model of coronary restenosis

    Circulation

    (2001)
  • M.-K. Hong et al.

    Paclitaxel coating reduces in-stent intimal hyperplasia in human coronary arteries

    Circulation

    (2003)
  • J.E. Sousa et al.

    Clinical investigation and reports-sustained suppression of neointimal proliferation by sirolimus-eluting stents: one-year angiographic and intravascular ultrasound follow-up

    Circulation

    (2001)
  • J.I. Rotmans et al.

    Sirolimus-eluting stents to abolish intimal hyperplasia and improve flow in porcine arteriovenous grafts

    Circulation

    (2005)
  • J.E. Sousa et al.

    Lack of neointimal proliferation after implantation of sirolimus-coated stents in human coronary arteries

    Circulation

    (2001)
  • T.C. Woods et al.

    Drug-eluting stents

    Annu. Rev. Med.

    (2004)
  • I. Iakovou et al.

    Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents

    JAMA

    (2005)
  • Cited by (42)

    • Polymer-based microneedle composites for enhanced non-transdermal drug delivery

      2022, Applied Materials Today
      Citation Excerpt :

      Polymer-based MN composites can also be attached to a woven surgical mesh for perivascular medication administration. Lee et al. also created polymer-based MN composites attached to mesh and wrapped around the damaged blood vessel throughout treatment using a rabbit aorta [140]. The polymeric MNs pierced the vascular tissue and touched the tunica media, allowing for targeted drug delivery.

    View all citing articles on Scopus
    1

    These two authors contributed equally to this work, thus should be considered co-first authors.

    View full text