Christopher J. Bettinger

Engineering Substrate Topography at the Micro- and Nanoscale to Control Cell Function

The interaction of mammalian cells with nanoscale topography has proven to be an important signaling modality in controlling cell function. Naturally occurring nanotopographic structures within the extracellular matrix present surrounding cells with mechanotransductive cues that influence local migration, cell polarization, and other functions. Synthetically nanofabricated topography can also influence cell morphology, alignment, adhesion, migration, proliferation, and cytoskeleton organization. We review the use of in vitro synthetic cell-nanotopography interactions to control cell behavior and influence complex cellular processes, including stem-cell differentiation and tissue organization. Future challenges and opportunities in cell-nanotopography engineering are also discussed, including the elucidation of mechanisms and applications in tissue engineering.

Accordion-like honeycombs for tissue engineering of cardiac anisotropy.

Tissue engineered grafts may be useful in myocardial repair, however previous scaffolds have been structurally incompatible with recapitulating cardiac anisotropy. Utilizing microfabrication techniques, a novel accordion-like honeycomb microstructure was rendered in poly(glycerol sebacate) to yield porous, elastomeric 3-D scaffolds with controllable stiffness and anisotropy. Accordion-like honeycomb scaffolds with cultured neonatal rat heart cells demonstrated utility via: (1) closely matched mechanical properties compared to native adult rat right ventricular myocardium, with stiffnesses controlled by polymer curing time; (2) heart cell contractility inducible by electric field stimulation with directionally-dependent electrical excitation thresholds (p<0.05); and (3) greater heart cell alignment (p<0.0001) than isotropic control scaffolds. Prototype bilaminar scaffolds with 3-D interconnected pore networks yielded electrically excitable grafts with multi-layered neonatal rat heart cells. Accordion-like honeycombs can thus overcome principal structural-mechanical limitations of previous scaffolds, promoting the formation of grafts with aligned heart cells and mechanical properties more closely resembling native myocardium.

A biodegradable and biocompatible gecko-inspired tissue adhesive

There is a significant medical need for tough biodegradable polymer adhesives that can adapt to or recover from various mechanical deformations while remaining strongly attached to the underlying tissue. We approached this problem by using a polymer poly(glycerol-co-sebacate acrylate) and modifying the surface to mimic the nanotopography of gecko feet, which allows attachment to vertical surfaces. Translation of existing gecko-inspired adhesives for medical applications is complex, as multiple parameters must be optimized, including: biocompatibility, biodegradation, strong adhesive tissue bonding, as well as compliance and conformability to tissue surfaces. Ideally these adhesives would also have the ability to deliver drugs or growth factors to promote healing. As a first demonstration, we have created a gecko-inspired tissue adhesive from a biocompatible and biodegradable elastomer combined with a thin tissue-reactive biocompatible surface coating. Tissue adhesion was optimized by varying dimensions of the nanoscale pillars, including the ratio of tip diameter to pitch and the ratio of tip diameter to base diameter. Coating these nanomolded pillars of biodegradable elastomers with a thin layer of oxidized dextran significantly increased the interfacial adhesion strength on porcine intestine tissue in vitro and in the rat abdominal subfascial in vivo environment. This gecko-inspired medical adhesive may have potential applications for sealing wounds and for replacement or augmentation of sutures or staples.

Biodegradable poly(polyol sebacate) polymers

We have developed a family of synthetic biodegradable polymers that are composed of structural units endogenous to the human metabolism, designated poly(polyol sebacate) (PPS) polymers. Material properties of PPS polymers can be tuned by altering the polyol monomer and reacting stiochiometric ratio of sebacic acid. These thermoset networks exhibited tensile Youngs moduli ranging from 0.37+/-0.08 to 378+/-33 MPa with maximum elongations at break from 10.90+/-1.37% to 205.16+/-55.76%, and glass transition temperatures ranging from approximately 7-46 degrees C. In vitro degradation under physiological conditions was slower than in vivo degradation rates observed for some PPS polymers. PPS polymers demonstrated similar in vitro and in vivo biocompatibility compared to poly(L-lactic-co-glycolic acid) (PLGA).

Amino alcohol-based degradable poly(ester amide) elastomers

Currently available synthetic biodegradable elastomers are primarily composed of crosslinked aliphatic polyesters, which suffer from deficiencies including (1) high crosslink densities, which results in exceedingly high stiffness, (2) rapid degradation upon implantation, or (3) limited chemical moieties for chemical modification. Herein, we have developed poly(1,3-diamino-2-hydroxypropane-co-polyol sebacate)s, a new class of synthetic, biodegradable elastomeric poly(ester amide)s composed of crosslinked networks based on an amino alcohol. These crosslinked networks feature tensile Youngs modulus on the order of 1MPa and reversable elongations up to 92%. These polymers exhibit in vitro and in vivo biocompatibility. These polymers have projected degradation half-lives up to 20 months in vivo.

Interplay of biomaterials and micro-scale technologies for advancing biomedical applications.

Micro-scale technologies have already dramatically changed our society through their use in the microelectronics and telecommunications industries. Today these engineering tools are also useful for many biological applications ranging from drug delivery to DNA sequencing, since they can be used to fabricate small features at a low cost and in a reproducible manner. The discovery and development of new biomaterials aid in the advancement of these micro-scale technologies, which in turn contribute to the engineering and generation of new, custom-designed biomaterials with desired properties. This review aims to present an overview of the merger of micro-scale technologies and biomaterials in two-dimensional (2D) surface patterning, device fabrication and three-dimensional (3D) tissue-engineering applications.

Biodegradable xylitol-based elastomers: In vivo behavior and biocompatibility

Biodegradable elastomers based on polycondensation reactions of xylitol with sebacic acid, referred to as poly(xylitol sebacate) (PXS) elastomers have recently been developed. We describe the in vivo behavior of PXS elastomers. Four PXS elastomers were synthesized, characterized, and compared with poly(L-lactic-co-glycolic acid) (PLGA). PXS elastomers displayed a high level of structural integrity and form stability during degradation. The in vivo half-life ranged from approximately 3 to 52 weeks. PXS elastomers exhibited increased biocompatibility compared with PLGA implants.

Zero-order controlled release of ciprofloxacin-HCl from a reservoir-based, bioresorbable and elastomeric device.

A reservoir-based device constructed of a completely biodegradable elastomer can enable several new implantation and insertion options for localized drug therapy, particularly in the case of urological therapies. We performed an in vitro performance evaluation of an implantable, bio-resorbable device that supplies short-term controlled release of ciprofloxacin-HCl (CIP). The proposed device functions through a combination of osmosis and diffusion mechanisms to release CIP for short-term therapies of a few weeks duration. Poly(glycerol-co-sebacic acid) (PGS) was cast in a tubular geometry with solid drug powder packed into its core and a micro-machined release orifice drilled through its wall. Drug release experiments were performed to determine the effective release rate from a single orifice and the range of orifice sizes in which controlled zero-order release was the main form of drug expulsion from the device. It is demonstrated that PGS is sufficiently permeable to water to allow the design of an elementary osmotic pump for drug delivery. Indeed, PGSs water permeability is several orders of magnitude larger than commonly used cellulose acetate for elementary osmotic pumps.

In vitro and in vivo degradation of poly(1,3-diamino-2-hydroxypropane-co- polyol sebacate) elastomers

Biomaterials with a wide range of tunable properties are desirable for application-specific purposes. We have previously developed a class of elastomeric poly(ester amides) based on the amine alcohol 1,3-diamino-2-hydroxypropane termed poly(1,3-diamino-2-hydroxypropane-co-polyol sebacate) or APS. In this work, we have synthesized and characterized formulations of APS polymers and studied the degradation of these polymers in vitro and in vivo. It was found that the chemical, physical, and mechanical properties of APS polymers could be tuned by adjusting monomer feed ratios and polymerization conditions. The degradation kinetics could also be greatly influenced by altering the formulation of APS polymers. In vivo degradation half-lives ranged from 6 to approximately 100 weeks. Furthermore, the dominant degradation mechanism (i.e. hydrolytic or enzymatic) could be controlled by adjusting the specific formulation of the APS polymer. On the basis of the observed in vitro and in vivo biodegradation phenomena, we also propose that the primary modes of degradation are composition dependent.

Advances in Materials and Structures for Ingestible Electromechanical Medical Devices

Ingestible biomedical devices that diagnose, prevent, or treat diseases has been a dream of engineers and clinicians for decades. The increasing apparent importance of gut health on overall well-being and the prevalence of many gastrointestinal diseases have renewed focus on this emerging class of medical devices. Several prominent examples of commercially successful ingestible medical devices exist. However, many technical challenges remain before ingestible medical devices can achieve their full clinical potential. This Minireview summarizes recent discoveries in this interdisciplinary topic including novel materials, advanced materials processing techniques, and select examples of integrated ingestible electromechanical systems. After a brief historical perspective, these topics will be reviewed with a dedicated focus on advanced functional materials and fabrication strategies in the context of clinical translation and potential regulatory considerations. Future perspectives, challenges, and opportunities related to ingestible medical devices will also be summarized.