The majority of cardiovascular devices are permanent and, with a few exceptions, are nondegradable. In general, these devices successfully fulfill their primary indication for use. However, permanent implants can also elicit a foreign-body response and are susceptible to infection and chronic inflammation. These issues compromise implant performance, raise healthcare costs, and increase patient morbidity.
Representing a new generation of implants, regenerative medical devices offer an innovative mode of treatment to regenerate, rather than simply repair, tissues and organs. Taking concepts from tissue engineering, these implants are degradable and promote new tissue growth. As the implant is absorbed, endogenous cells replace the form and function of the device, leaving the patient with solely biological tissue. With this new paradigm, regenerative implants have the potential to address unmet needs and previously untreatable conditions.
However, designing a regenerative medical implant requires new design considerations that are absent from traditional, nondegradable implants. Both the engineering and biological implications of the implant must be considered. This article discusses how to use textile engineering and advanced biomaterials to address these additional design requirements. Additionally, examples are given on developing a regenerative vascular graft for each design consideration.
Form and Functionality
It may seem obvious, but a regenerative medical device should perform the same primary function as a permanent implant. For example, a regenerative vascular graft must act as a conduit for the flow of blood, the same as any non-degradable vascular graft. However, a regenerative (degradable) implant must address both form and function. Over time, the implant converts to biological tissue that has the same cells and is indistinguishable from surrounding, native tissue. A reparative (nondegradable) implant does not change and only addresses primary function.
Why does this matter? In the case of a blood vessel, the primary function is to transport blood throughout the body. Yet, blood vessels also serve a multitude of secondary functions to maintain homeostasis (e.g., change blood pressure, alter blood flow, control blood clotting). Current nonliving, nondegradable vascular grafts are unable to successfully address these secondary functions. This limits their utility to the repair of large diameter vessels (>6 mm). 1 By designing a vascular graft that regenerates a new blood vessel, new indications are possible, including off-the-shelf grafts for pediatric patients or coronary artery bypass grafting (CABG).
Designing the Implant Macrostructure
How does one start to design a regenerative medical device? A primary consideration is the device macrostructure. The regenerative implant should act as a template or scaffold for new tissue growth. To create scaffolds, textile engineering offers a highly flexible and reproducible method of manufacturing that can easily be scaled up. Here, flexibility means two different things:
Flexibility in manufacturing — Core textile technologies consist of weaving, knitting, and braiding. This versatility allows for a multitude of 2D and 3D structures with wide ranges in mechanical properties.
Flexibility in structure — Even though the biomaterial used to make a textile may be a rigid thermoplastic, the resulting structures are inherently flexible and formable. The secret is in the interplay of yarn and textile forming parameters.
In the example of vasculature, blood vessels naturally expand and contract during pulsatile blood flow. When designing a structure for regenerative vascular grafts, maypole braiding is a rational choice. Maypole braiding can create hollow lumens that radially distend and contract (think of Chinese finger traps) while maintaining mechanical strength and flexibility. By incorporating this dynamic behavior into the medical device, regeneration of form and function (primary and secondary) can be improved. 2 , 3
Designing the Implant Microstructure
While a textile structure directs tissue formation on the macro scale, yarn morphology and design can influence cell behavior at the micro scale. Yarn is comprised of filaments and filament bundles in a manner similar to skeletal muscle structure. These filaments can be extruded to a variety of sizes, from millimeters to microns in diameter. There are two design considerations when choosing the yarn:
Filament structure — Typical filaments are extruded with circular cross-sections. However, advances in extrusion technology offer new possibilities in filament design. Fractal, flat, square, and triangular geometries are just a few examples that can influence yarn packing and porosity.
Yarn structure — Yarn is formed as a monofilament or multifilament. Monofilament yarns are stiffer and present less drag and friction during textile manufacturing. Multifilament yarns are more pliable and can provide greater tensile strength.
In the case of a regenerative implant, cell infiltration and adhesion into the structure are necessary to initiate tissue growth. Here, multifilament yarns would be preferred due to the presence of surface texture and porosity. With better integration of cells, multifilament yarns can provide greater tissue anchorage, which will be important as the textile structure degrades over time.
Implant Degradation Time Frame
The key to a regenerative medical device is its degradation properties. As a temporary device, the degradation rate must match the rate of new tissue formation. The device should maintain function or partial function until new tissue can dominate the overall structure. This may be the hardest design requirement to fulfill. If the device degrades too fast, there will be implant failure and a loss of function. If the devices degrades too slowly, unnecessary or chronic inflammation will be a detriment to the regeneration of new tissue.
Biomaterial selection will largely determine the degradation time frame of the implant. For example, polyglycolides (PGA) degrade within a few months whereas polycaprolactones degrade within a few years. Yet, post-processing techniques can also be utilized to optimize polymer degradation:
Thermal annealing — By heat treating the textile structure at an appropriate temperature and duration, the scaffold degradation time frame can be increased.
Fiber extrusion — Biomaterial degradation rates can also be varied during the fiber extrusion process by changing how the yarn is drawn and collected.
Sterilization — The method of sterilization needs to be considered, since this processing step typically shortens the degradation time frame.
During the development of a textile vascular graft, PGA is a potential biomaterial of choice due to its degradation time frame. To ensure that the implant does not degrade too quickly, the textile graft can be heat treated to increase PGA crystallinity. This post-processing technique would prolong the degradation and allow the scaffold to retain enough mechanical strength before new tissue replaces graft function.
Coatings and Surface Treatments
Coatings and surface treatments are common methods used to incorporate additional functionality and improve implant performance. In order to regenerate new tissue, the implant surface must be amenable for cell attachment and growth. Plasma and corona treatments are versatile methods for changing implant surface chemistry. In fact, plasma treatment is the preferred method to modify tissue culture plastics for improved cell culture.
The selection of a coating material will depend on the intended application. Oftentimes, degradable coatings are used to release drugs, such as in drug-eluting stents. However, degradable coatings can also be used to augment regeneration.
In the case of developing a vascular graft, a coating could be necessary to make the textile graft blood-tight while maintaining implant flexibility. Regenerez®, a biodegradable elastomer made from polyglycerol sebacate, can satisfy these design constraints. Regenerez is fast degrading, elastic, and surface degrading. With its unique degradation properties, cells can infiltrate the graft and gradually allow a transition of blood-sealing properties from PGS to native tissue.
Regenerative medical devices represent a new generation of implants for the treatment of diseased or damaged organs. By combining textile engineering capabilities and advanced biomaterials optimization, the design of these implants can be tailored for proper tissue regeneration. Already, early preclinical studies have demonstrated the utility of a Regenerez-coated PGA graft for the regeneration of small-diameter vessels. Overall, novel regenerative devices can offer avenues to fulfill unmet needs and untapped market opportunities.
This article was written by Steven Lu, PhD, Senior Scientist, and Jeremy Harris, PhD, Director of Research, The Secant Group, LLC, Telford, PA. For more information, visit here.