Joerg Lahann

Physical approaches to biomaterial design

The development of biomaterials for drug delivery, tissue engineering and medical diagnostics has traditionally been based on new chemistries. However, there is growing recognition that the physical as well as the chemical properties of materials can regulate biological responses. Here, we review this transition with regard to selected physical properties including size, shape, mechanical properties, surface texture and compartmentalization. In each case, we present examples demonstrating the significance of these properties in biology. We also discuss synthesis methods and biological applications for designer biomaterials, which offer unique physical properties.

Synthetic polymer coatings for long-term growth of human embryonic stem cells

We report a fully defined synthetic polymer coating, poly[2-(methacryloyloxy)ethyl dimethyl-(3-sulfopropyl)ammonium hydroxide] (PMEDSAH), which sustains long-term human embryonic stem (hES) cell growth in several different culture media, including commercially available defined media. The development of a standardized, controllable and sustainable culture matrix for hES cells is an essential step in elucidating mechanisms that control hES cell behavior and in optimizing conditions for biomedical applications of hES cells.

Ultrasmall implantable composite microelectrodes with bioactive surfaces for chronic neural interfaces

Implantable neural microelectrodes that can record extracellular biopotentials from small, targeted groups of neurons are critical for neuroscience research and emerging clinical applications including brain-controlled prosthetic devices. The crucial material-dependent problem is developing microelectrodes that record neural activity from the same neurons for years with high fidelity and reliability. Here, we report the development of an integrated composite electrode consisting of a carbon-fibre core, a poly(p-xylylene)-based thin-film coating that acts as a dielectric barrier and that is functionalized to control intrinsic biological processes, and a poly(thiophene)-based recording pad. The resulting implants are an order of magnitude smaller than traditional recording electrodes, and more mechanically compliant with brain tissue. They were found to elicit much reduced chronic reactive tissue responses and enabled single-neuron recording in acute and early chronic experiments in rats. This technology, taking advantage of new composites, makes possible highly selective and stealthy neural interface devices towards realizing long-lasting implants.

Red blood cell-mimicking synthetic biomaterial particles

Biomaterials form the basis of current and future biomedical technologies. They are routinely used to design therapeutic carriers, such as nanoparticles, for applications in drug delivery. Current strategies for synthesizing drug delivery carriers are based either on discovery of materials or development of fabrication methods. While synthetic carriers have brought upon numerous advances in drug delivery, they fail to match the sophistication exhibited by innate biological entities. In particular, red blood cells (RBCs), the most ubiquitous cell type in the human blood, constitute highly specialized entities with unique shape, size, mechanical flexibility, and material composition, all of which are optimized for extraordinary biological performance. Inspired by this natural example, we synthesized particles that mimic the key structural and functional features of RBCs. Similar to their natural counterparts, RBC-mimicking particles described here possess the ability to carry oxygen and flow through capillaries smaller than their own diameter. Further, they can also encapsulate drugs and imaging agents. These particles provide a paradigm for the design of drug delivery and imaging carriers, because they combine the functionality of natural RBCs with the broad applicability and versatility of synthetic drug delivery particles.

Physical aspects of cell culture substrates: topography, roughness, and elasticity.

The cellular environment impacts a myriad of cellular functions by providing signals that can modulate cell phenotype and function. Physical cues such as topography, roughness, gradients, and elasticity are of particular importance. Thus, synthetic substrates can be potentially useful tools for exploring the influence of the aforementioned physical properties on cellular function. Many micro- and nanofabrication processes have been employed to control substrate characteristics in both 2D and 3D environments. This review highlights strategies for modulating the physical properties of surfaces, the influence of these changes on cell responses, and the promise and limitations of these surfaces in in-vitro settings. While both hard and soft materials are discussed, emphasis is placed on soft substrates. Moreover, methods for creating synthetic substrates for cell studies, substrate properties, and impact of substrate properties on cell behavior are the main focus of this review.

Concise Review: The Evolution of human pluripotent stem cell culture: From feeder cells to synthetic coatings†‡§

Current practices to maintain human pluripotent stem cells (hPSCs), which include induced pluripotent stem cells and embryonic stem cells, in an undifferentiated state typically depend on the support of feeder cells such as mouse embryonic fibroblasts (MEFs) or an extracellular matrix such as Matrigel. Culture conditions that depend on these undefined support systems limit our ability to interpret mechanistic studies aimed at resolving how hPSCs interact with their extracellular environment to remain in a unique undifferentiated state and to make fate‐changing lineage decisions. Likewise, the xenogeneic components of MEFs and Matrigel ultimately hinder our ability to use pluripotent stem cells to treat debilitating human diseases. Many of these obstacles have been overcome by the development of synthetic coatings and bioreactors that support hPSC expansion and self‐renewal within defined culture conditions that are free from xenogeneic contamination. The establishment of defined culture conditions and synthetic matrices will facilitate studies to more precisely probe the molecular basis of pluripotent stem cell self‐renewal and differentiation. When combined with three‐dimensional cultures in bioreactors, these systems will also enable large‐scale expansion for future clinical applications. STEM Cells2013;31:1–7

Derivation of Mesenchymal Stem Cells from Human Induced Pluripotent Stem Cells Cultured on Synthetic Substrates

Human‐induced pluripotent stem cells (hiPSCs) may represent an ideal cell source for research and applications in regenerative medicine. However, standard culture conditions that depend on the use of undefined substrates and xenogeneic medium components represent a significant obstacle to clinical translation. Recently, we reported a defined culture system for human embryonic stem cells using a synthetic polymer coating, poly[2‐(methacryloyloxy)ethyl dimethyl‐(3‐sulfopropyl)ammonium hydroxide] (PMEDSAH), in conjunction with xenogeneic‐free culture medium. Here, we tested the hypothesis that iPSCs could be maintained in an undifferentiated state in this xeno‐free culture system and subsequently be differentiated into mesenchymal stem cells (iPS‐MSCs). hiPSCs were cultured on PMEDSAH and differentiated into functional MSCs, as confirmed by expression of characteristic MSC markers (CD166+, CD105+, CD90+,CD73+, CD31−, CD34−, and CD45−) and their ability to differentiate in vitro into adipogenic, chondrogenic, and osteoblastic lineages. To demonstrate the potential of iPS‐MSCs to regenerate bone in vivo, the newly derived cells were induced to osteoblast differentiation for 4 days and transplanted into calvaria defects in immunocompromised mice for 8 weeks. MicroCT and histologic analyses demonstrated de novo bone formation in the calvaria defects for animals treated with iPS‐MSCs but not for the control group. Moreover, positive staining for human nuclear antigen and human mitochondria monoclonal antibodies confirmed the participation of the transplanted hiPS‐MSCs in the regenerated bone. These results demonstrate that hiPSCs cultured in a xeno‐free system have the capability to differentiate into functional MSCs with the ability to form bone in vivo. STEM CELLS2012;30:1174–1181

Bioactive immobilization of r-hirudin on CVD-coated metallic implant devices

The poor biocompatibility of metallic coronary stents which leads to un-satisfying restenosis rates is mainly caused by contact activation of blood cells, smooth muscle cells and endothelial cells. Mimicking a metal surface with a biocompatible coating that actively suppresses mechanisms leading to restenosis may overcome todays limitations regarding the complications of metal stents. Nitinol coronary stents were coated by CVD polymerization of functionalized [2.2]paracyclophanes. The monomers 4-amino [2.2]paracyclophane, 4-hydroxy methyl [2.2]paracyclophane and [2.2]paracyclophane-4,5,12,13-tetracarboxylic acid dianhydride were previously synthesized. A suitable installation for the CVD polymerization procedure was designed and used for the polymerization procedures. Physical and chemical properties of the polymers were shown to fulfill the requirements regarding the application as a stent coating material. The functional groups of the polymer coatings were used for the immobilization of the thrombin inhibitor r-hirudin. In vitro results indicate that the bioactively coated stents are less thrombogenic than virgin metallic stents. Surface-bound r-hirudin decreases platelet adhesion drastically due to interactions between platelets and r-hirudin.

Towards Designer Microparticles: Simultaneous Control of Anisotropy, Shape, and Size

Biodegradable, compositionally anisotropic microparticles with two distinct compartments that exhibit controlled shapes and sizes are fabricated. These multifunctional particles are prepared by electrohydrodynamic co-jetting of poly(lactide-co-glycolide) polymer solutions. By varying different solution and process parameters, namely, concentration and flow rate, a variety of non-equilibrium bicompartmental shapes, such as discoid and rod-shaped microparticles are produced in high yields. Optimization of jetting parameters, combined with filtration, results in near-perfect, bicompartmental spherical particles in the size range of 3-5 microm. Simultaneous control over anisotropy, size, shape, and surface structure provides an opportunity to create truly multifunctional microparticles for a variety of biological applications, such as drug delivery, diagnostic assays, and theranostics.

From Advanced Biomedical Coatings to Multi‐Functionalized Biomaterials

In this review, current activities in the development of active biomaterials related to bio‐interfacial design as well as novel concepts for smart polymer systems are highlighted. For instance, advanced biomedical coatings, including vapor‐based polymer coatings for the controlled attachment of biomolecules, and temperature‐responsive coatings for tissue engineering are outlined. Moreover, recent trends with the fabrication of “smart,” switchable surfaces, such as conformationally switching monolayers, will be reviewed. Specific focus will further be given to multi‐functionalized biomaterials including shape‐memory polymers that undergo specific changes in shape in response to stimuli like heat or light. This novel class of intelligent materials highlights a recent trend in biomaterial development targeting is the extension of this concept to multi‐functionalization. In particular, the combination of biodegradability and shape‐memory effects opens a range of opportunities for biomedical applications including intelligent sutures or stents.