In vivo tissue engineering: Part I. Concept genesis and guidelines for its realization.

A loss of function of an organ often represents a life-threatening situation. Transplantations are successful, but "replacement" availability, its compatibility with the host, and subsequent healing often pose serious questions. Tissue engineering, where a carefully prepared scaffold is populated, in vitro, by cells to form an artificial organ, addresses some of the problems mentioned above. Trauma associated with the implant introduction to the host often complicates the process. The novel concept of in vivo tissue engineering which is designed to mediate the healing and tissue regeneration process by providing an in vitro formed porous, microcellular scaffold is proposed. The scaffold (part or entire organ) is then populated by cells either spontaneously (the surrounding cells will spread and populate to inhabit the scaffold) or by cellular augmentation (encapsulated cells are delivered to this in statu nascendi scaffold). Minimally traumatic arthroscopic surgery combined with a unique polymer delivery system is envisioned for the introduction of this implant to a site to be repaired. Such an approach will require the formation of polymer in-situ, in a reasonable time. The scaffold-forming polymers will be, in principle, biodegradable. We propose to utilize biodegradable polyurethane systems for in vivo tissue engineering. Diversity of their structure/property relationships, relative "ease" of their preparation, and excellent biocompatibility predetermine polyurethanes to be the materials of choice. This paper describes the genesis of this concept and potentials for its realization. It is intended to initiate and stimulate discussion among the related scientific disciplines to form a basis for this field. The synthesis, application, and biodegradation of selected polyurethanes and variety of its medical utilization will be discussed in upcoming papers.

Biomedical applications of polyurethanes: a review of past promises, present realities, and a vibrant future.

Polyurethanes, having extensive structure/property diversity, are one of the most bio- and blood-compatible materials known today. These materials played a major role in the development of many medical devices ranging from catheters to total artificial heart. Properties such as durability, elasticity, elastomer-like character, fatigue resistance, compliance, and acceptance or tolerance in the body during the healing, became often associated with polyurethanes. Furthermore, propensity for bulk and surface modification via hydrophilic/hydrophobic balance or by attachments of biologically active species such as anticoagulants or biorecognizable groups are possible via chemical groups typical for polyurethane structure. These modifications are designed to mediate and enhance the acceptance and healing of the device or implant. Many innovative processing technologies are used to fabricate functional devices, feeling and often behaving like natural tissue. The hydrolytically unstable polyester polyurethanes were replaced by more resistant but oxidation-sensitive polyether polyols based polyurethanes and their clones containing silicone and other modifying polymeric intermediates. Chronic in vivo instability, however, observed on prolonged implantation, became a major roadblock for many applications. Presently, utilization of more oxidation resistant polycarbonate polyols as soft segments, in combination with antioxidants such as Vitamin E, offer materials which can endure in the body for several years. The applications cover cardiovascular devices, artificial organs, tissue replacement and augmentation, performance enhancing coatings and many others. In situ polymerized, cross-linked systems could extend this biodurability even further. The future will expand this field by revisiting chemically-controlled biodegradation, in combination with a mini-version of RIM technology and minimally invasive surgical procedures, to form, in vivo, a scaffold, by delivery of reacting materials to the specific site in the body and polymerizing the mass in situ. This scaffold will provide anchor for tissue regeneration via cell attachment, proliferation, control of inflammation, and healing.

Small caliber vascular grafts. Part II: Polyurethanes revisited.

Polyurethanes are considered to be one of the most bio- and blood-compatible biomaterials known today. By intelligent utilization of principles governing the structure/property relationship of these polymers, one can generate systems which resemble, in principle, the physical-mechanical behavior of living tissue. Thus, it is not surprising that these materials played a major role in development of small caliber vascular grafts targeted for vascular access, peripheral and coronary artery bypass indications. Numerous technologies, often esoteric in nature, were and are utilized to generate porous, potentially multilayered conduits possessing some or many characteristics of natural blood vessels. Properties such as durability, elasticity, compliance, pulsatility, and propensity for healing became attainable via polyurethanes. Furthermore, additional surface and/or bulk modification via attachments of biologically active species such as anticoagulants, cell proliferation suppressants, anti-infective compounds or biorecognizable groups are possible due to reactive groups which are part of the polyurethane structure. These modifications are designed to control or mediate host acceptance and healing of the graft. Finally, a myriad of practical processing technologies are used to fabricate functional grafts. Among those, casting, electrostatic and wet spinning of fibers and monofilaments, extrusion, dip coating or spraying of mandrels with polymer/additive solutions are often coupled with chemical-potential-difference-driven coagulation and phase inversion leading to grafts feeling and often behaving like natural vessels. Historically, the first polyurethanes utilized were hydrolytically unstable polyester polyurethanes containing hydrolysis-prone polyester polyols as soft segments, followed by hydrolytically stable but oxidation sensitive polyether polyols based polyurethanes. Polyether-based polyurethanes and their clones containing silicone and other modifying polymeric intermediates represented significant progress. Many viable technologies were discovered and developed using polyether-based polyurethanes. Chronic in vivo instability observed on prolonged implantation became, however, a major roadblock. The path led finally to the use of hydrolytically and oxidatively stable polycarbonate polyols as the soft segment to generate biodurable materials with resistance to biodegradation adequate for vascular access or perhaps peripheral graft indications. This biodurability needs to be further increased in order to utilize the full potential of polyurethanes in development of patent small caliber graft. Modification of both the soft and hard segments needs to be considered in order to maximize biodurability of both basic building blocks of the polyurethane. This paper reviews the achievements, discusses trends, and offers the view of the future in this exciting area of material/device combination.

Small caliber vascular grafts. Part I: state of the art.

Vascular grafts, devices designed to augment inefficiently functioning vascular systems, represent a significant part of implantable medical devices, with major participation in over a million vascular surgeries performed worldwide. By definition accepted in the art, a small caliber graft is a conduit with internal diameter (ID) of 6 mm or less; large caliber grafts start at ID of 7 mm. While the autologous grafts utilizing saphenous veins (SVG) and internal iliac, or mammary arteries are used exclusively in cardiac artery bypass grafts (CABG) procedures and preferentially in many peripheral indications, and while the use of grafts with biological origin did not proliferate, polymer-based artificial grafts of controlled patterns and porosity are prostheses of choice for the large caliber. The polyester (PET) yarn is knitted or woven into various porous patterns. The PTFE tubes are expanded into porous conduits (ePTFE). Although these technologies are used to produce the grafts with ID larger than 6 mm, the dominant principles are being applied to the development of small caliber graft. Polyurethanes are also evaluated for small caliber application. The grafts (regardless of the ID) produced by the above technologies are porous. This porosity, considered to be critical for proper healing and overall graft patency, causes the blood to leak through the graft wall or at anastomosis through the suture holes. Both the wall leakage and suture hole bleeding remain rather serious drawbacks. Currently, collagen, gelatin, albumin and their derivatives are used as sealants. Various modes of application and degrees of crosslinking are utilized to control in vivo degradation and graft healing. Other hydrogels, both natural and synthetic, could play significant roles as sealants and modifiers of the graft performance. Enhancement of graft patency via improvement of initial hemocompatibility could be achieved by application of bioactive coatings. Heparinized systems seem to dominate in this field, but many new concepts are being investigated. Intraluminal endothelialization via mediating biologicals could open significant potential for synthetic small caliber grafts. Furthermore, porous biodegradable tubes could be used as temporary scaffold to attract and promote cell propagation and ingrowth, the true angiogenesis. Part I of this series discusses the "S.O.T.A" of the small caliber graft. The following parts will discuss concepts needed for development of truly patent small caliber grafts and will report on our progress in the development of biodurable and pulsatile grafts for vascular access, peripheral, and potentially for CABG indications.

Bulk, surface, and blood-contacting properties of polyetherurethanes modified with polyethylene oxide.

The bulk, surface, and blood-contacting properties of a series of polyether polyurethanes based on polyethylene oxide (PEO) (MW = 1450), polytetramethylene oxide (PTMO) (MW = 1000), and mixed PEO/PTMO soft segments were evaluated. The effect of varying the weight percentage of PEO, and thus the overall polarity of the mixed soft segment phase, was investigated. Two polymer blends prepared from a PTMO-based and a PEO-based polyurethane were also studied. Differential scanning calorimetry (DSC) and dynamic mechanical analysis indicated that the polyurethanes based on either the PEO or the PTMO soft segments are relatively phase mixed. The degree of phase mixing in the polymers increased with increasing weight fraction of PEO. As expected, water absorption and the hydrophilicity of the polymer increased with increasing PEO soft segment content. In vacuum, the PEO-rich polymers have a lower concentration of soft segment at the surface, possibly due to the migration of the polar PEO segments away from the polymer/vacuum interface. The blood-contacting results indicated that the higher PEO-containing polymers were more thrombogenic than the pure PTMO-based polyurethane. A threshold concentration of PEO in the polyurethane appeared to be required before the blood-contacting properties were significantly affected.

Bulk, surface and blood-contacting properties of polyether polyurethanes modified with polydimethylsiloxane macroglycols.

The bulk, surface and blood-contacting properties of a series of polyether polyurethanes, modified with three different polydimethylsiloxane (PDMS) macroglycol segments, were evaluated. The PDMS oligomers were terminated with hydroxy-tipped end groups of varying polarity. The effect of substituting the polytetramethylene oxide (PTMO) soft segment of a base polyurethane with 5 and 15 wt% of these PDMS-containing polyols was investigated. The ultimate tensile strength and elongation at break appeared to be the bulk properties most significantly affected by the addition of the PDMS-containing polyols. Underwater contact angle data indicate that the block copolymer surface became more hydrophilic with increasing PDMS content. In a vacuum, as determined from the ESCA data, the relatively non-polar PDMS soft segments preferentially oriented at the surface with increasing PDMS incorporation. Despite the variation in the surface properties, the blood compatibility of these polymers was not significantly affected by the addition of the PDMS-containing polyols.

Softening of thermoplastic polyurethanes: a structure/property study.

Softening of thermoplastic polyurethanes (TPU) in a simulated body environment (37 degrees C n-saline) was studied as a function of composition, structure and resultant morphology of these (AB)n type block copolymers. The structural variations were attempted by changing chemical composition and molecular weight of both hard A and soft B segments and their weight ratio in the polymer. In addition, the influence of bulk and/or surface modifiers, such as "reacted-in" polysiloxanes and fluorinated polyalkylether glycols, was also investigated. The degree of softening, expressed as a percentage decrease of the elastic modulus (5% tensile modulus) upon two hours exposure to the testing environment, is significant, reversible and depends on the ratio of hard to soft segment and the extent of microphase separation. Since these parameters can be selected during the polymer synthesis and processing into desirable shapes, the degree of softening can thus be controlled. This softening at body temperature represents one of the most notable performance advantages of these biomaterials.