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Monthly Spin-Off #4 [The Future of Drug Delivery]

Can Targeted Drug Delivery Help the Body Heal?

Bio-Spun™ Materials Integrated with Drug Help Healing

Medical Devices: Need and Composition


The human body is an amazing “machine,” having the ability to heal itself under different circumstances such as a broken bone, being sick with a common virus, a cut in the skin, or even something more extreme such as liver damage. The body inherently has many complex built-in processes that allow it to heal. In spite of this capability, there are many circumstances when the body cannot heal itself, resulting in the need to use a medical device to assist in the healing process. Approximately 10% of all Americans have a medical device implanted into their body, which translates to over 32 million people in the United States alone having one or more devices[1]. These devices can range from such simple devices as suture, tooth fillings, hernia repair mesh, wound dressings and catheter cuffs to more complex implantable devices such as the total implantable heart, left ventricular assist devices and prosthetic arterial grafts. Many of the materials comprising current medical devices use materials that you come across in your daily routines for non-medical applications such as woven, braided, or knitted textiles such as polyester, cotton and nylon, non-stick films and materials such as Teflon, materials with stretch such as polyurethane (Spandex) and degradable materials (cosmetic face masks).


Complications Associated with Devices

Although utilization of these devices has improved the quality of life for an aging patient population, all medical devices are prone to two major complications: incomplete healing and device infection. The body’s cells have many roles and responsibilities. For example, the cells lining your arteries allow your blood to flow and if the artery gets damaged, the cells look to repair the vessel. For synthetic materials, the normal cells that would normally be within the body do not exist. Additionally, the structures of these materials do not encourage the body’s cells to grow into them. This incomplete healing can result in major complications such as surface blood clot formation, overgrowth of an inappropriate cell type resulting in blockage or activation of blood that normally does not occur with a normal artery. Surgical site infections account for approximately 14-16% of the 2.4-million hospital-borne infections in the United States, resulting in increased patient morbidity and mortality. The inherent bulk properties of various biomaterials that comprise these devices provide a “perfect” environment for initial bacterial/fungus adhesion with subsequent biofilm production and growth.


Since biomaterials are comprised of foreign polymeric materials, cellular components normally present within native tissue are not available for controlling and/or regulating the reparative process. A commonality among these complications is that currently available biomaterials do not emulate the multitude of dynamic biologic and reparative processes that occur in normal tissue. Thus, development of a novel biomaterial that would direct or enhance some of the normal healing processes of native tissue would improve patient morbidity and mortality upon implantation of these devices.


Rationale for Using Electrospinning to Produce Next Generation of Medical Devices


Electrospinning is an inexpensive and scalable technique for synthesizing nanofibrous materials for tissue engineered scaffolds and drug delivery systems[2],[3],[4],[5]. Our proprietary technology produces materials (Bio-Spun™) that structurally resemble the body’s natural scaffold that cells grow into, known as extracellular matrix.(Figure 1).

This structure has been shown by our group and others[6] to encourage tissue integration. Additionally, our Bio-Spun™ materials have been shown to have significantly less scar formation (fibrosis) when implanted in the body as compared to materials that comprise these devices today. Data shared in the next section will clearly demonstrate the benefit of Bio-Spun™ material.



Even with the benefits of improved healing of our Bio-Spun™ material, there are circumstances that can place a medical device at a disadvantage such as implantation into an infected area, use in an area of low or turbulent blood flow or placement into a patient with reduced healing capabilities (i.e. patient with diabetes, heart disease). Bio-Spun™ materials are manufactured at room temperature and can therefore easily incorporate drugs and/or other bioactive agents directly into the nanofibers. Many existing materials/coatings such polymer films, 3-D printed materials and extruded yarns must be manufactured at high temperatures, compromising drug viability, resulting in potentially rigid structures, and limited healing resulting from using the delivery vehicle. Newer, protein-based drugs are especially sensitive to higher temperatures making it impossible to use traditional deposition and other methods to incorporate them into devices for delivery. Bio-Spun™ materials can also incorporate and release hard-to-dissolve drugs, expanding the potential for promising drug candidates to be commercially viable. BioSurfaces has evluated types of drugs/active agents such as antimicrobial agents (i.e. synthetic/naturally-occurring), anti-coagulants,

anti-proliferative agents, anti-inflammatory agents, anti-fibrotic agents, imaging agents, additives (i.e. nanosilver, bioglass), antifungal agents, growth factors and genetic sequences (i.e. siRNA)








From Benchtop to Preclinical: Drug-Loaded Bio-Spun™ Materials Provide Targeted Delivery and Improved Outcomes


Over the past almost 20 years, BioSurfaces has developed and refined its technology related to drug incorporation into its Bio-Spun™ materials for various applications. We have also worked with different partners, both large and small companies, focused on treating diseases of the heart, gastrointestinal tract, retina, kidney and peripheral arteries. There is no better feeling when an outside group conducts tests on our Bio-Spun™ materials, sharing the positive data that has been generated. While BioSurfaces has generated a significant amount of data related to drug incorporation and release, this report will cover two specific complications related to current materials: infection and clot formation due to a lack of healing.


To prevent infection, a broad-spectrum antibiotic was incorporated into our Bio-Spun™ material. Non-drug and antibiotic-loaded Bio-Spun™ materials in the form of a circular cuff to repair heart valves (BioCuff) were made. These materials, when exposed to simulated arterial blood flow, showed that antibiotic-loaded BioCuff materials had controlled, sustained release of the drug over a 30-day period as shown in zone of inhibition testing (Figure 2). These clear zones around the drug-loaded materials revealed that bacteria were being killed away from the device and not allowed to grow on the device surface. The antibiotic-loaded Bio-Spun™ materials were then implanted over 21 days in a preclinical model designed to provide a significant bacterial challenge (Figure 3). These studies showed that the antibiotic-loaded materials prevented infection of the device and surrounding area while permitting tissue ingrowth as compared to the standard clinical woven PET control, which was completely infiltrated with bacteria and had no healing.

To prevent surface blood clot formation, an anti-clotting (anti-coagulant) drug was incorporated into Bio-Spun™ PET. Simulated arterial flow conditions were then applied to woven PET, Bio-Spun™ PET without drug and Bio-Spun™ PET with an anti-clotting agent to evaluate drug release and subsequent activity using a challenging whole blood clotting test. These benchtop studies showed that even after washing for 7. 14 and 28 days, the drug-loaded Bio-Spun™ PET materials continued to prevent surface clot formation as compared to current woven PET materials as well as in non-drug loaded Bio-Spun™ PET (Figure 4). These same materials were then implanted into a small preclinical model to assess the body’s reaction to the respective materials for time periods up to 60 days (Figure 5). Woven PET materials, which are used in current devices, elicited a significant inflammatory response with limited healing occurring between the fiber bundles. In contrast, both control and drug-loaded Bio-Spun™ materials had minimal inflammatory response with excellent healing. Presence of the drug did not affect overall healing.


Come Work with Us


BioSurfaces is seeking to expand the use of its platform technology through strategic relationships, R&D contracting and other arrangements. We have the ability to provide a sustainable solution for a partner’s product life cycle and beyond using our agile and flexible process, as well as advanced technologies available for license or sale. To learn more, please contact us at info@biosurfaces.us.







References

--------------------------------------------------------------------------------------------------------------------------------------------- [1] Salazar L. Addressing the Medical Device Safety Crisis. The Regulatory Review 2021. www.theregreview.org/2021/10/27/salazar-addressing-medical-device-safetycrisis/#:~:text=Roughly%2010%20percent—or%20approximately,have %20an%20 implanted%20medical%20device. [2] Persano L, Camposeo A, Tekmen C, Pisignano D. Industrial Upscaling of Electrospinning and Applications of Polymer Nanofibers: A Review. Macromol Mater Eng 2013;298(5):504–520. [3] Xu X, Yang Q, Wang Y, Hu H, Chen X, Jing X. Biodegradable electrospun poly(L-lactide) fibers containing antibacterial silver nanoparticles. Eur Polymer J 2006;42(9):2081-2087. [4] Kim K, Luu YK, Chang C, Fang D, Hsiao BS, Chu B, Hadjiargyrou M. Incorporation and controlled release of a hydrophilic antibiotic using poly(lactide-coglycolide)-based electrospun nanofibrous scaffolds. J Control Rel 2004;98(1):47-56. [5] Zeng J, Xu X, Chen X, Liang Q, Bian X, Yang L, Jing X. Biodegradable electrospun fibers for drug delivery. J Control Rel 2003;92(3):227-31. [6] Li W.J., Laurencin C.T., Caterson E.J., Tuan R.S., Ko F.K. Electrospun nanofibrous structure: A novel scaffold for tissue engineering. J Biomed Mater Res 2002;60(4):613-21.



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