Challenges related to development of bioabsorbable vascular stents.

Vascular stents have revolutionised the field of interventional cardiology. Once an artery has healed, however, stents are no longer thought to serve a functional role. Bioabsorbable stents would be preferred to permanent implants if they maintain arterial architecture, minimise device/host interactions, and reduce the need for long-term anticoagulation therapy. Technical challenges to develop and commercialise a successful bioabsorbable stent relate to identification of materials and stent designs capable of balancing acute and chronic mechanical properties, degradation time, and biocompatibility. Successful programs will be ones that achieve these requirements with uncompromised product deliverability, efficacy and safety. Many materials currently proposed for use in bioabsorbable stents take longer than 24 months to degrade and so may not meet these criteria. We describe here the Medtronic CardioVascular bioabsorbable program which focuses on developing a degradable stent for superficial femoral arteries that targets degradation in less than 12 months.

The use of temperature-composition combinatorial libraries to study the effects of biodegradable polymer blend surfaces on vascular cells.

Controlling cellular and physiological responses such as adhesion, proliferation and migration is a highly desirable feature of engineered scaffolds. One important application would be the design of tissue engineered vascular grafts that regulate cell adhesion and growth. We utilized temperature-composition combinatorial polymer libraries to investigate the effects of surfaces of blended poly(D,L-lactic-co-glycolic acid) (PLGA) and poly(epsilon-caprolactone) (PCL) on murine vascular smooth muscle cells (SMC). In this manner, SMCs were exposed to approximately 1000 distinguishable surfaces in a single experiment, allowing the discovery of optimal polymer compositions and processing conditions. SMC adhesion, aggregation, proliferation, and protein production were highest in regions with mid- to high-PCL concentrations and high annealing temperatures. These regions exhibited increased surface roughness, increased microscale PLGA-rich matrix stiffness, and significant change of bulk PCL-rich crystallinity relative to other library regions. This study revealed a previously unknown processing temperature and blending composition for two well-known polymers that optimized SMC interactions.

Viscoelastic testing methodologies for tissue engineered blood vessels.

In order to function in vivo, tissue engineered blood vessels (TEBVs) must encumber pulsatile blood flow and withstand hemodynamic pressures for long periods of time. To date TEBV mechanical assessment has typically relied on single time point burst and/or uniaxial tensile testing to gauge the strengths of the constructs. This study extends this analysis to include creep and stepwise stress relaxation viscoelastic testing methodologies. TEBV models exhibiting diverse mechanical behaviors as a result of different architectures ranging from reconstituted collagen gels to hybrid constructs reinforced with either untreated or glutaraldhyde-crosslinked collagen supports were evaluated after 8 and 23 days of in vitro culturing. Data were modeled using three and four-parameter linear viscoelastic mathematical representations and compared to porcine carotid arteries. While glutaraldhyde-treated hybrid TEBVs exhibited the largest overall strengths and toughness, uncrosslinked hybrid samples exhibited time-dependent behaviors most similar to native arteries. These findings emphasize the importance of viscoelastic characterization when evaluating the mechanical performance of TEBVs. Limits of testing methods and modeling systems are presented and discussed.

Incorporation of intact elastin scaffolds in tissue-engineered collagen-based vascular grafts.

Although collagen-based tissue-engineered blood vessels (TEBVs) have many interesting properties and have been utilized to study aspects of vascular biology, these constructs are too weak to be implanted as bypass grafts for in vivo investigations. This study presents a method to incorporate organized, intact elastin into collagen-based TEBVs to form hybrid constructs that better mimic arterial physiology and exhibit improved mechanical properties. Porcine carotids were digested with a series of autoclave and chemical treatments to elicit isolated elastin scaffolds. Elastin purity was verified via immunohistochemistry and amino acid analysis. Isolated scaffolds were combined with type I collagen and either human dermal fibroblasts (HDFs) or rat smooth muscle cells (RASMs) to form an elastin hybrid TEBV. Hybrid constructs exhibited increased tensile strengths (11-fold in HDFs; 7.5-fold in RASMs) and linear stiffness moduli (4-fold in HDFs; 1.8-fold in RASMs) compared with collagen control constructs with no exogenous elastin scaffold. Viscoelastic properties of the TEBVs also improved with the addition of an ancillary elastin scaffold as determined through stepwise stress relaxation analysis. Whereas the majority of resistance to deformation in collagen control constructs stemmed from viscous fluidlike effects, elastin hybrid constructs exhibited more ideal elastic solid mechanical behavior. Thus, elastin scaffolds can help recreate the elastic properties of native arteries. Future challenges include stimulating appropriate reorganization or synthesis of the collagen matrix to provide the necessary strength and viscoelastic properties for implantation.

Designer blood vessels and therapeutic revascularization.

Inadequate vascular perfusion leads to fatal heart attacks, chronic ulcers, and other serious clinical conditions. The body's capacity to restore vascular perfusion through angiogenesis and arteriogenesis is often impaired by pre-existing disease, and availability of native replacements for nonfunctional arteries is limited in many patients. Thus, recreating blood vessels of various calibres through novel engineering technologies has emerged as a radical option among therapeutic strategies for revascularization. Ranging from artificial, recycled or reassembled natural conduits to sophisticated microdevices, we refer to these as 'designer blood vessels'. Our common efforts to continuously improve vascular replacement design have provided many clues about our own blood vessels, but nature's ability to create nonthrombogenic, immunocompatible, strong, yet biologically responsive blood vessels remains unparalleled. Just as art reproductions never equal the original masterpiece, designer blood vessels may never attain nature's perfection. Nevertheless, they will provide a valuable option as long as they come close enough and are available to many.

A biological hybrid model for collagen-based tissue engineered vascular constructs.

Various approaches to tissue engineering a small diameter blood vessel have historically relied upon extended culturing periods and/or synthetic materials to create mechanical properties suitable to withstand the hemodynamic stresses of the vasculature. In this work, we present the concept of a construct-sleeve hybrid (CSH) graft, which uses a biological support to provide temporary reinforcement while cell-mediated remodeling of the construct occurs. Support sleeves were fabricated from Type I collagen gels and crosslinked with glutaraldehyde, ultraviolet, or dehydrothermal treatments. Uniaxial tensile testing of acellular sleeves revealed increased stiffness moduli and tensile stresses with crosslinking treatments. A second collagen layer containing cells was molded about the sleeve to create a CSH. After in vitro culture, CHSs with uncrosslinked (UnXL) and glutaraldehyde treated (Glut) sleeves exhibited significant increases in mechanical strength (20.4-fold and 121-fold increases in ultimate stress, respectively) compared to unreinforced control constructs. Burst testing produced similar findings with peak pressures of 100 and 650mmHg in the UnXL and Glut CSHs, respectively. Construct compaction, cell viability, and histological examination demonstrated that the function of most cells remained unimpaired with the incorporation of the biological support sleeve.