Bioresorbable Vascular Grafts Research Articles

Fabrication and mechanical characterization of near field electrospun bioresorbable vascular grafts with fibrous architecture mimicking the arterial extracellular matrix

Cardiovascular disease, arteriosclerosis, is characterized by the thickening of blood vessel (arteries) walls restricting blood flow and is a global health problem. One treatment option is a surgical procedure utilizing an autologous or synthetic vascular graft to bypass or replace the diseased arterial segment. The goal of this study was to fabricate and mechanically characterize near field electrospun bioresorbable vascular grafts with a fibrous architecture that mimics the arterial extracellular matrix. Polydioxanone vascular constructs with circumferential fiber alignment angles of 15°/75° and 30°/60° (0° representing circumferential fiber alignment) were fabricated using a custom built near-field electrospinning (NFES) system. The vascular construct mechanical properties were compared to the saphenous vein (SV) and internal mammary artery (IMA) through longitudinal and circumferential uniaxial mechanical testing, suture retention, and burst pressure evaluations. The results demonstrated that the 15°/75° templates were closest to mimicking the native vessel target properties as compared to the 30°/60°; however, neither of the vascular template designs achieved or exceeded all the target values. For the ultimate tensile strength, both the constructs met the SV value on the circumferential axis (2.61 MPa) and the IMA value on the longitudinal axis (4.3 MPa). In terms of suture retention, the 15°/75° template was the only construct that was in the IMA and SV targeted range of 138–200 gf. Finally, the burst pressure testing results indicated that neither of the vascular constructs achieved the level of the SV or IMA (1600–3196 mmHg), however, the 15° constructs were within the lower error of the SV. In conclusion, with further design modifications, NFES constructs have demonstrated promise as small-diameter vascular grafts by mimicking native arterial architecture and mechanical properties.

Preparation and performance of random- and oriented-fiber membranes with core-shell structures via coaxial electrospinning.

The cells and tissue in the human body are orderly and directionally arranged, and constructing an ideal biomimetic extracellular matrix is still a major problem to be solved in tissue engineering. In the field of the bioresorbable vascular grafts, the long-term functional prognosis requires that cells first migrate and grow along the physiological arrangement direction of the vessel itself. Moreover, the graft is required to promote the formation of neointima and the development of the vessel walls while ensuring that the whole repair process does not form a thrombus. In this study, poly (l-lactide-co-ε-caprolactone) (PLCL) shell layers and polyethylene oxide (PEO) core layers with different microstructures and loaded with sodium tanshinone IIA sulfonate (STS) were prepared by coaxial electrospinning. The mechanical properties proved that the fiber membranes had good mechanical support, higher than that of the human aorta, as well as great suture retention strengths. The hydrophilicity of the oriented-fiber membranes was greatly improved compared with that of the random-fiber membranes. Furthermore, we investigated the biocompatibility and hemocompatibility of different functional fiber membranes, and the results showed that the oriented-fiber membranes containing sodium tanshinone IIA sulfonate had an excellent antiplatelet adhesion effect compared to other fiber membranes. Cytological analysis confirmed that the functional fiber membranes were non-cytotoxic and had significant cell proliferation capacities. The oriented-fiber membranes induced cell growth along the orientation direction. Degradation tests showed that the pH variation range had little change, the material mass was gradually reduced, and the fiber morphology was slowly destroyed. Thus, results indicated the degradation rate of the oriented-fiber graft likely is suitable for the process of new tissue regeneration, while the random-fiber graft with a low degradation rate may cause the material to reside in the tissue for too long, which would impede new tissue reconstitution. In summary, the oriented-functional-fiber membranes possessing core-shell structures with sodium tanshinone IIA sulfonate/polyethylene oxide loading could be used as tissue engineering materials for applications such as vascular grafts with good prospects, and their clinical application potential will be further explored in future research.

Evaluation of human umbilical vein endothelial cells growth onto heparin-modified electrospun vascular grafts

One of the main challenges of cardiovascular tissue engineering is the development of bioresorbable and compliant small-diameter vascular grafts (SDVG) for patients where autologous grafts are not an option. In this work, electrospun bilayered bioresorbable SDVG based on blends of poly(L-lactic acid) (PLLA) and segmented polyurethane (PHD) were prepared and evaluated. The inner layer of these SDVG was surface-modified with heparin, following a methodology involving PHD urethane functional groups. Heparin was selected as anticoagulant agent, and also due to its ability to promote human umbilical vein endothelial cells (HUVECs) growth and to inhibit smooth muscle cells over-proliferation, main cause of neointimal hyperplasia and restenosis. Immobilized heparin was quantified and changes in SDVG microstructure were investigated through SEM. Tensile properties of the heparin-functionalized SDVG resembled those of saphenous vein. Vascular grafts were seeded with HUVECs and cultured on a flow-perfusion bioreactor to analyze the effect of heparin on graft endothelization under simulated physiological-like conditions. The analysis of endothelial cells attachment and gene expression (Real-Time PCR) pointed out that the surface functionalization with heparin successfully promoted a stable and functional endothelial cell layer.

Bioresorbable Polymeric Scaffold in Cardiovascular Applications.

Advances in material science and innovative medical technologies have allowed the development of less invasive interventional procedures for deploying implant devices, including scaffolds for cardiac tissue engineering. Biodegradable materials (e.g., resorbable polymers) are employed in devices that are only needed for a transient period. In the case of coronary stents, the device is only required for 6–8 months before positive remodelling takes place. Hence, biodegradable polymeric stents have been considered to promote this positive remodelling and eliminate the issue of permanent caging of the vessel. In tissue engineering, the role of the scaffold is to support favourable cell-scaffold interaction to stimulate formation of functional tissue. The ideal outcome is for the cells to produce their own extracellular matrix over time and eventually replace the implanted scaffold or tissue engineered construct. Synthetic biodegradable polymers are the favoured candidates as scaffolds, because their degradation rates can be manipulated over a broad time scale, and they may be functionalised easily. This review presents an overview of coronary heart disease, the limitations of current interventions and how biomaterials can be used to potentially circumvent these shortcomings in bioresorbable stents, vascular grafts and cardiac patches. The material specifications, type of polymers used, current progress and future challenges for each application will be discussed in this manuscript.

Imatinib attenuates neotissue formation during vascular remodeling in an arterial bioresorbable vascular graft

BackgroundBioresorbable vascular grafts (BVGs) can transform biologically into active blood vessels and represent an alternative to traditional synthetic conduits, which are prone to complications such as infection and thrombosis. Although platelet-derived growth factors and c-Kit positive cells play an important role in smooth muscle cell (SMC) migration and proliferation in vascular injury, atherosclerosis, or allograft, their roles in the vascular remodeling process of an arterial BVG remains unknown. Thus, we assessed the neottisue formation on arterial BVG remodeling by administrating imatinib, which is both a platelet-derived growth factor receptor kinase inhibitor and c-Kit receptor kinase inhibitor, in a murine model. MethodsBVGs were composed of an inner poly(L-lactic-co-ε-caprolactone) copolymer sponge layer and an outer electrospun poly(L-lactic acid) nanofiber layer, which were implanted into the infrarenal abdominal aortas of C57BL/6 mice. After graft implantation, saline or 100 mg/kg of imatinib was administrated intraperitoneally daily for 2 weeks (n = 20 per group). Five mice in each group were scheduled to be humanely killed at 3 weeks and 15 at 8 weeks, and BVGs were explanted for histologic assessments. ResultsGraft patency during the 8-week observational period was not significantly different between groups (control, 86.7% vs imatinib, 80.0%; P > .999). Neotissue formation consisting of endothelialization, smooth muscle proliferation, and deposition of collagen and elastin was not observed in either group at 3 weeks. Similar endothelialization was achieved in both groups at 8 weeks, but thickness and percent area of neotissue formation were significantly higher in the control group than in the imatinib group, (thickness, 30.1 ± 7.2 μm vs 19.6 ± 4.5 μm [P = .001]; percent area, 9.8 ± 2.7% vs 6.8 ± 1.8% [P = .005]). Furthermore, SMC layer and deposition of collagen and elastin were better organized at 8 weeks in the control group compared with the imatinib group. The thickness of SMC layer and collagen fiber area were significantly greater at 8 weeks in the control group than in the imatinib group (P < .001 and P = .026, respectively). Because there was no difference in the inner diameter of explanted BVGs (831.7 ± 63.4 μm vs 841.8 ± 41.9 μm; P = .689), neotissue formation was thought to advance toward the outer portion of the BVG with degradation of the polymer scaffold. ConclusionsImatinib attenuates neotissue formation during vascular remodeling in arterial bioresorbable vascular grafts (BVGs) by inhibiting SMC layer formation and extracellular matrix deposition.

Elasticity response of electrospun bioresorbable small-diameter vascular grafts: Towards a biomimetic mechanical response

The elasticity response of synthetic vascular grafts is very important for the grafts long term success. Natural arteries possess a characteristic response to internal pressure, known as J-curve. Mimicking this feature is believed to be the path to obtain a vascular graft that does not fail over time. In this work, two synthetic bioresorbable polymers were selected to design small-diameter vascular grafts (SDVGs) based on their biomimetic mechanical response. Poly(l-lactic acid) (PLLA) was chosen for its similar response to collagen and a segmented poly(ester urethane) (PHD) was used to introduce elastomeric properties through its elastin-like behavior. A bilayered electrospun conduit with two different PLLA/PHD blends was fabricated by mimicking the natural collagen-to-elastin ratio in the media and adventitia layers. The biomimetic mechanical response, compliance and elastic modulus were studied under pulsated pressure conditions. The grafts nanofibrous morphology as well as its layered structure resulted in properties promising for bypass applications.

Tissue-Engineered Vascular Graft of Small Diameter Based on Electrospun Polylactide Microfibers.

Tubular vascular grafts 1.1 mm in diameter based on poly(L-lactide) microfibers were obtained by electrospinning. X-ray diffraction and scanning electron microscopy data demonstrated that the samples treated at T = 70°C for 1 h in the fixed state on a cylindrical mandrel possessed dense fibrous structure; their degree of crystallinity was approximately 44%. Strength and deformation stability of these samples were higher than those of the native blood vessels; thus, it was possible to use them in tissue engineering as bioresorbable vascular grafts. The experiments on including implantation into rat abdominal aorta demonstrated that the obtained vascular grafts did not cause pathological reactions in the rats; in four weeks, inner side of the grafts became completely covered with endothelial cells, and fibroblasts grew throughout the wall. After exposure for 12 weeks, resorption of PLLA fibers started, and this process was completed in 64 weeks. Resorbed synthetic fibers were replaced by collagen and fibroblasts. At that time, the blood vessel was formed; its neointima and neoadventitia were close to those of the native vessel in structure and composition.

Tropoelastin inhibits intimal hyperplasia of mouse bioresorbable arterial vascular grafts.

Small resorbable vascular grafts can block due to the over-proliferation of smooth muscle cells in neointimal hyperplasia. We show here that the proliferation of these cells is restricted in this type of graft. This is achieved with a simple dip, non-covalent coating of tropoelastin. It is in principle amendable to other grafts and is therefore an attractive process. This study is particularly significant because: (1) it shows that smooth muscle cell proliferation can be reduced while still accommodating the growth of endothelial cells, (2) small vascular grafts with an internal diameter of less than 1mm are amenable to this process, and (3) this process works for resorbable grafts.

Abstract 11205: Tropoelastin Inhibits Intimal Hyperplasia of Mouse Bioresorbable Arterial Vascular Grafts

Introduction: Neointimal hyperplasia, which results from the activation, proliferation and migration of vascular smooth muscle cells (SMCs), is a detrimental condition for vascular stents or vascular grafts that leads to stenosis. Preventing neointimal hyperplasia is critically important for the success of arterial vascular grafts. Hypothesis: We assessed the hypothesis that tropoelastin seeding will prevent SMC proliferation and neointimal hyperplasia in bioresorbable arterial vascular grafts. Methods: Poly (glycolic acid) (PGA) fiber mesh coated with poly (l-lactic-co- ε -caprolactone) (PLCL) scaffolds reinforced by poly (l-lactic acid) (PLA) nano-fibers were prepared as bioresorbable arterial grafts. Tropoelastin was then seeded onto the luminal surfaces of the grafts. Female C57BL/6 mice were randomly divided into 2 groups: 1. Tropoelastin seeded group (n=10), and 2. Unseeded group (n=10). The grafts were implanted as infra-renal aortic interposition conduits. Animals were followed for 8 weeks then sacrificed to evaluate neotissue formation. Results: Tropoelastin treatment substantially reduced the number of cells that stained positive for SMC (α-SMA) and Proliferating cell nuclear antigen (PCNA) in the vessel walls (Unseeded group: 60 ± 36/HPF vs. Tropoelastin seeded group: 21 ± 13/HPF, P =0.048, Unseeded group: 11.0 ± 5.6 /HPF vs. Tropoelastin seeded group: 4.8 ± 1.7/HPF, P =0.043, SMC and PCNA, respectively, HPF; high power field) (Fig. A, B). Tropoelastin significantly reduced the thickness of the intimal layer (Unseeded group: 91 ± 22 μm vs. Tropoelastin seeded group: 50 ± 11 μm, P =0.004) (Fig. C). Conclusions: Tropoelastin seeding is beneficial in preventing SMC proliferation and neointimal hyperplasia in bioresorbable arterial vascular grafts.

Fast-degrading bioresorbable arterial vascular graft with high cellular infiltration inhibits calcification of the graft

ObjectiveBioresorbable vascular grafts are biologically active grafts that are entirely reconstituted by host-derived cells through an inflammation-mediated degradation process. Calcification is a detrimental condition that can severely affect graft performance. Therefore, prevention of calcification is of great importance to the success of bioresorbable arterial vascular grafts. The objective of this study was to test whether fast-degrading (FD) bioresorbable arterial grafts with high cellular infiltration will inhibit calcification of grafts. MethodsWe created two versions of bioresorbable arterial vascular grafts, slow-degrading (SD) grafts and FD grafts. Both grafts had the same inner layer composed of a 50:50 poly(l-lactic-co-ε-caprolactone) copolymer scaffold. However, the outer layer of SD grafts was composed of poly(l-lactic acid) nanofiber, whereas the outer layer of FD grafts was composed of a combination of poly(l-lactic acid) and polyglycolic acid nanofiber. Both grafts were implanted in 8- to 10-week-old female mice (n = 15 in the SD group, n = 10 in the FD group) as infrarenal aortic interposition conduits. Animals were observed for 8 weeks. Resultsvon Kossa staining showed calcification in 7 of 12 grafts in the SD group but zero in the FD group (P < .01, χ2 test). The cell number in the outer layer of FD grafts was significantly higher than in the SD grafts (SD, 0.87 ± 0.65 × 103/mm2; FD, 2.65 ± 1.91 × 103/mm2; P = .02). ConclusionsThe FD bioresorbable arterial vascular graft with high cellular infiltration into the scaffold inhibited calcification of grafts.

Novel Bioresorbable Vascular Graft With Sponge-Type Scaffold as a Small-Diameter Arterial Graft

Current commercialized small-diameter arterial grafts have not shown clinical effectiveness due to their poor patency rates. The present study evaluated the feasibility of an arterial bioresorbable vascular graft, which has a porous sponge-type scaffold, as a small-diameter arterial conduit. The grafts were constructed by a 50:50 poly (1-lactic-co-ε-caprolactone) copolymer (PLCL) scaffold reinforced by a poly (1-lactic acid) (PLA) nanofiber. The pore size of the PLCL scaffold was adjusted to a small size (12.8 ± 1.85 μm) or a large size (28.5 ± 5.25 μm). We compared the difference in cellular infiltration, followed by tissue remodeling, between the groups. The grafts were implanted in 8- to 10-week-old female mice (n= 15 in each group) as infrarenal aortic interposition conduits. Animals were monitored for 8 weeks and euthanized to evaluate neotissue formation. No aneurysmal change or graft rupture was observed in either group. Histologic assessment demonstrated favorable cell infiltration into scaffolds, neointimal formation with endothelialization, smooth muscle cell proliferation, and elastin deposition in both groups. No significant difference was observed between the groups. Immunohistochemical characterization with anti-F4/80 antibody demonstrated that macrophage infiltration into the grafts occurred in both groups. Staining for M1 and M2, which are the two major macrophage phenotypes, showed no significant difference between groups. Our novel bioresorbable vascular grafts showed well-organized neointimal formation in the high-pressure arterial circulation environment. The large-pore scaffold did not improve cellular infiltration and neotissue formation compared with the small-pore scaffold.

Cilostazol, Not Aspirin, Prevents Stenosis of Bioresorbable Vascular Grafts in a Venous Model.

Despite successful translation of bioresorbable vascular grafts for the repair of congenital heart disease, stenosis remains the primary cause of graft failure. In this study, we investigated the efficacy of long-term treatment with the antiplatelet drugs, aspirin and cilostazol, in preventing stenosis and evaluated the effect of these drugs on the acute phase of inflammation and tissue remodeling. C57BL/6 mice were fed a drug-mixed diet of aspirin, cilostazol, or normal chow during the course of follow-up. Bioresorbable vascular grafts, composed of poly(glycolic acid) mesh sealed with poly(l-lactide-co-ε-caprolactone), were implanted as inferior vena cava interposition conduits and followed up for 2 weeks (n=10 per group) or 24 weeks (n=15 per group). Both aspirin and cilostazol suppressed platelet activation and attachment onto the grafts. On explant at 24 weeks, well-organized neotissue had developed, and cilostazol treatment resulted in 100% graft patency followed by the aspirin (67%) and no-treatment (60%) groups (P<0.05). Wall thickness and smooth muscle cell proliferation in the neotissue of the cilostazol group were decreased when compared with that of the no-treatment group at 24 weeks. In addition, cilostazol was shown to have an anti-inflammatory effect on neotissue at 2 weeks by regulating the recruitment and activation of monocytes. Cilostazol prevents stenosis of bioresorbable vascular graft in a mouse inferior vena cava implantation model up to 24 weeks and is accompanied by reduction of smooth muscle cell proliferation and acute inflammation.

Characterizing bone marrow-derived mast cell interaction with electrospun bioresorbable vascular grafts (INM2P.436)

Abstract Upon implantation, the regenerative potential of a vascular graft will be dependent on the body’s innate immune response. Thus, it is imperative to evaluate and regulate how innate immune cells interact with a vascular graft’s structural architecture. Different pore-sizes and fiber diameters of electrospun grafts should modulate mast cell activation and secretion, thus dictating their innate ability for inflammation or angiogenesis and regeneration. Grafts were electrospun with two different polymer concentrations on a solid mandrel, an air-impedance mandrel (increasing scaffold porosity), and altered by compression (decreasing scaffold porosity). Murine bone marrow-derived mast cells (BMMC) were seeded on scaffolds, and supernatants and cell lysates were collected after LPS and IL-33-mediated activation. ELISA analysis demonstrated that BMMC released TNFα and IL-6 at significantly greater concentrations on grafts with decreased fiber diameter and porosity. This was matched by greater NFκB activation, as measured by western blotting. In contrast, significantly greater VEGF secretion was observed on grafts with the largest fiber diameter and porosity. These results indicate that graft architecture regulates mast cell interactions and subsequent potential for healing, with increased fiber diameter and porosity promoting an anti-inflammatory and angiogenic response.

Modulation, mechanism and angiogenic potential of macrophage polarization (M1/M2) on electrospun bioresorbable vascular grafts

Modulation, mechanism and angiogenic potential of macrophage polarization (M1/M2) on electrospun bioresorbable vascular grafts

The use of air-flow impedance to control fiber deposition patterns during electrospinning

Electrospun non-woven structures have the potential to form bioresorbable vascular grafts that promote tissue regeneration in situ as they degrade and are replaced by autologous tissue. Current bioresorbable grafts lack appropriate regeneration potential since they do not have optimal architecture, and their fabrication must be altered by the manipulation of process parameters, especially enhancing porosity. We describe here an air-impedance process where the solid mandrel is replaced with a porous mandrel that has pressurized air exiting the pores to impede fiber deposition. The mandrel design, in terms of air-flow rate, pore size, and pore distribution, allows for control over fiber deposition and scaffold porosity, giving greater cell penetration without a detrimental loss of mechanical properties or structural integrity.

Modulation of mast cell adhesion, proliferation, and cytokine secretion on electrospun bioresorbable vascular grafts

Mast cells synthesize several potent angiogenic factors and can also stimulate fibroblasts, endothelial cells, and macrophages. An understanding of how they participate in wound healing and angiogenesis is important to further our knowledge about in situ vascular prosthetic regeneration. The adhesion, proliferation, and cytokine secretion of bone marrow-derived murine mast cells (BMMC) on electrospun polydioxanone, polycaprolactone, and silk scaffolds, as well as tissue culture plastic, has been investigated in the presence or absence of IL-3, stem cell factor, IgE and IgE with a crosslinking antigen, dinitrophenol-conjugated albumin (DNP). It was previously believed that only activated BMMCs exhibit adhesion and cytokine secretion. However, this study shows nonactivated BMMC adhesion to electrospun scaffolds. Silk scaffold was not found to be conducive for mast cell adhesion and cytokine secretion. Activation by IgE and DNP significantly enhanced mast cell adhesion, proliferation, migration, and secretion of tumor necrosis factor alpha, macrophage inflammatory protein-1α, and IL-13. This indicates that mast cells might play a role in the process of biomaterial integration into the host tissue, regeneration, and possibly angiogenesis.

Creating small diameter bioresorbable vascular grafts through electrospinning

Seamless, non-woven, bioresorbable vascular prosthetics composed of sub-micron fibers have been successfully created through electrospinning. These prosthetics have proven to be both bioactive and mechanically viable during in vitro testing, and hold great potential to be conducive to in situ tissue engineering/regeneration in the future.

Characterization of smooth muscle cells on poly(ε-caprolactone) films

Bioresorbable vascular grafts can be used for direct implantation. Over time, the grafts will degrade and be replaced by natural tissue. In this study, the potential application of biaxially drawn poly(ε-caprolactone) (PCL) films for the design of vascular grafts was examined. PCL films were first modified to enhance cell physiological response to the surface. Two methods of surface modification were studied: surface hydrolysis by immersion in sodium hydroxide, and immobilization of collagen onto PCL film surface. Tensile tests indicate that immersion in sodium hydroxide results in a significant drop in ultimate tensile strength, whereas collagen-immobilized films remained uncompromised. Human coronary artery smooth muscle cells were cultured on the different surfaces, and it was demonstrated that collagen-immobilized films elicited the most favorable response from the cultured cells. This indicates the potential for collagen-immobilized PCL films for vascular tissue engineering applications.

Electrospun polydioxanone–elastin blends: potential for bioresorbable vascular grafts**Disclosure. Several authors have United States and International patents pending concerning technology presented in this article, and this technology has been licensed to NanoMatrix, Inc., in which several authors have a financial interest.

An electrospun cardiovascular graft composed of polydioxanone (PDO) and elastin has been designed and fabricated with mechanical properties to more closely match those of native arterial tissue, while remaining conducive to tissue regeneration. PDO was chosen to provide mechanical integrity to the prosthetic, while elastin provides elasticity and bioactivity (to promote regeneration in vitro/in situ). It is the elastic nature of elastin that dominates the low-strain mechanical response of the vessel to blood flow and prevents pulsatile energy from being dissipated as heat. Uniaxial tensile and suture retention tests were performed on the electrospun grafts to demonstrate the similarities of the mechanical properties between the grafts and native vessel. Dynamic compliance measurements produced values that ranged from 1.2 to 5.6%/100 mmHg for a set of three different mean arterial pressures. Results showed the 50:50 ratio to closely mimic the compliance of native femoral artery, while grafts that contained less elastin exceeded the suture retention strength of native vessel. Preliminary cell culture studies showed the elastin-containing grafts to be bioactive as cells migrated through their full thickness within 7 days, but failed to migrate into pure PDO scaffolds. Electrospinning of the PDO and elastin-blended composite into a conduit for use as a small diameter vascular graft has extreme potential and warrants further investigation as it thus far compares favorably to native vessel.

Modeling the transmural stress distribution during healing of bioresorbable vascular prostheses.

Little attention has been given to the stresses within the wall of bioresorbable vascular prostheses and how they might affect the resorption process. We modeled the graft "complex" (inner tissue capsule, residual graft, and outer tissue capsule) as a three-layered compound tube under internal pressure. Using this biomechanical model, we studied the effects of alterations in the geometry (i.e., radius and thickness) and mechanical properties of each stratum on the overall transmural stress distribution. Hypothetical simulations were performed to investigate the possible sequence of and alterations in the radial and circumferential stresses during the resorption process. Our results suggest that early in the resorption phase, the inner tissue capsule is subjected to compressive hoop stresses and concentrated, large-magnitude compressive radial stresses. This distribution gives way to the more typical distribution for a thick-walled tube when equilibration (i.e., complete resorption) is approached. The prediction of the compressive stresses in the pseudo-intima during early resorption parallels findings of an elevated mitotic index in that region at that time. This leads to a new hypothesis, namely, that compressive stresses, both in-plane and out-of-plane with respect to the regenerated vascular cells, participate in the resorption process of bioresorbable vascular grafts by modulating elevated cellular proliferative activity and may play an important role in other aspects of vascular cell biology. Results of recent experimentation support this hypothesis.