Buddy D. Ratner

Central nervous system (CNS) diseases and injuries might be treated by implanted devices, tissue regenerative scaffolds, or drug delivery platforms. However, inflammatory CNS responses limit these interventions and may worsen outcomes following damage to the CNS. Via the foreign body reaction, macrophages and glial cells trigger a “glial scar” around implants, reducing device performance, scaffold regenerative ability, or drug delivery potential. Previous studies have shown that stiffness of CNS implants significantly affects glial encapsulation, but few studies have investigated materials that truly match brain tissue stiffness. Porous precision‐templated scaffolds with uniform, interconnected, 40 µm spherical pores have shown favorable healing outcomes and a reduced foreign body reaction (FBR) in numerous soft and hard tissue applications. To quantify the effects of both hydrogel compliance (stiffness) and pore size on glial encapsulation, we implanted poly(2‐hydroxyethyl methacrylate‐co‐glycerol methacrylate) (pHEMA/GMA) scaffolds of varying stiffness and pore size for 4 weeks in rat brain. We observed reduced astrocyte encapsulation around porous templated scaffolds (PTS) compared to solid hydrogel rods, reduced pro‐inflammatory macrophage polarization for softer hydrogels versus stiffer hydrogels, and the presence of new blood vessels, neuronal markers, and neurogenesis within the pores. Utilizing soft, precision‐porous hydrogels could provide a strategy for mitigating glial scarring and improving regeneration in implant‐based CNS treatments.

Central nervous system diseases and injuries might be treated by implanted devices, tissue regenerative scaffolds, or drug delivery platforms. However, inflammatory CNS responses limit these interventions and may worsen outcomes following damage to the CNS. Via the foreign body reaction, macrophages and glial cells trigger a “glial scar” around implants, reducing device performance, scaffold regenerative ability, or drug delivery potential. Previous studies have shown that stiffness of CNS implants significantly affects glial encapsulation, but few studies have investigated materials that truly match brain tissue stiffness. Porous precision-templated scaffolds with uniform, interconnected, 40 µm spherical pores have shown favorable healing outcomes and a reduced FBR in numerous soft and hard tissue applications. To quantify the effects of both hydrogel compliance (stiffness) and pore size on glial encapsulation, we implanted poly(2-hydroxyethyl methacrylate-co-glycerol methacrylate) (pHEMA/GMA) scaffolds of varying stiffness and pore size for 4 weeks in rat brain. We observed reduced astrocyte encapsulation around PTS compared to solid hydrogel rods, reduced pro-inflammatory macrophage polarization for softer hydrogels versus stiffer hydrogels, and the presence of new blood vessels, neuronal markers and neurogenesis within the pores. Utilizing soft, precision-porous hydrogels could provide a strategy for mitigating glial scarring and improving regeneration in implant-based CNS treatments.

Hydrolytic and enzymatic degradation of linear segmented polyurethanes with differing compositions were studied by atomic force microscopy and time-of-flight secondary ion mass spectroscopy. Poly (ester urethane urea)s (PEUUs) with two different molecular ratios of polycaprolactone diol (PCL) soft segments and L-lysine diisocyanate/hydrazine hard segments were exposed to aqueous conditions (water or phosphate buffered saline), and the changes in their surface chemistry and morphology were studied. It was found that polymer surface roughness in aqueous conditions is significantly affected by its bulk composition. After soaking in an aqueous buffer solution, the surface of PEUU with higher PCL concentration became significantly rougher compared to PEUU with lower PCL concentration. This surface roughening can be attributed to PCL lost from the surface during hydrolytic degradation. Despite the surface roughness changes, the rate of the hydrolytic degradation of PEUUs was found to be independent of bulk polymer composition. Enzymatic degradation of a linear segmented PEUU containing an oligopeptide segment [poly(peptide urethane urea) (PPUU)] in a collagenase solution was also investigated. The PPUU oligopeptide segment contained proline, hydroxyproline, and glycine amino acids. In a collagenase solution, the PPUU polymer exhibited a significantly higher degradation rate and surface roughness compared to a PEUU polymer that did not contain the oligopeptide segment.

Precision porous scaffolds hold promise for tissue engineering and regenerative medicine due to their ability to support cell ingrowth and vascularization and mitigate the foreign body reaction (FBR). In previous work, we demonstrated that vat photopolymerization 3D printing enables the fabrication of porous scaffolds with 40 μm interconnected cubical pores. This study aims to do a preliminary evaluation of cellular responses and the FBR to 3D‐printed scaffolds with 40 μm cubical pores, in comparison with template‐fabricated spherical pores (optimized for healing) and non‐porous slabs (negative control). The results indicate that porous scaffolds, regardless of pore geometry, outperform non‐porous structures in mitigating the FBR, promoting tissue regeneration, and triggering vascularization. This is the first paper demonstrating the pro‐healing property of high‐resolution 3D‐printed 40 μm cubical pore scaffolds. These findings underscore the potential of 3D‐printed porous scaffolds to advance patient‐specific therapies, support soft (such as brain and blood vessel) and hard tissue (such as bone) repair, and improve healing outcomes in regenerative medicine applications.

Vat Photopolymerization (VPP) holds much promise for producing biomaterial constructs such as porous scaffolds. However, achieving micron-scale pore dimensions with precision presents a challenge. This study offers an innovative approach to stabilize the silicone elastomer vat surface permitting micron-scale layer thickness accuracy to be maintained. Internal and surface contamination on the poly(dimethyl siloxane) (PDMS) vat surface were observed and effectively controlled with a pre-saturation methodology, and porous structures with cubical pores were then printed with varying layer thicknesses. These structures demonstrate the ability to achieve micrometric resolution and layer thicknesses as fine as 32 µm. A scaffold suitable for in vivo implantation with 40 µm cubical pores was successfully printed within 5 hours using a stabilized PDMS vat surface. Additionally, the methodology’s adaptability to intricate non-linear edge porous structures underscores its versatility across X, Y, and Z-axis.

The University of Washington Engineered Biomaterials (UWEB) Engineering Research Center (ERC) was funded from 1996 to 2007 by the U.S. National Science Foundation. The mission of UWEB was to advance biomaterials by integrating modern biology with materials science. UWEB specifically focused on the healing and integration of medical implants. UWEB teamed biologists, physicians, engineers, and industry and demonstrated three paths that might advance biomaterials so they could seamlessly integrate and heal in the body. The three primary lines of investigation were precision porous scaffolds, super-non-fouling surfaces, and the control of matricellular proteins. The UWEB program set the groundwork for the modern field of immunoengineering. Also, UWEB invested significantly in training scientists/engineers who could freely integrate advances in biological sciences, state-of-the-art materials science, and medical technology. This historical summary of the UWEB program demonstrates that federal investment in interfacing forefront fields can yield dividends with benefits for society and the economy.

Diseases and traumatic injuries to the central nervous system (CNS) demand the development of new biomaterials to improve healing and treatment options. Matching material mechanical properties to specific tissues and optimizing material porous structures are central goals for improving biomaterials. However, biomaterials with both precision-controlled porous structures and brain-matched mechanical properties (low modulus) are still lacking. In this study, we developed soft hydrogel scaffolds with mechanical properties similar to that of CNS tissues, and a uniform 40 µm porous structure—40 µm pores have been shown to be optimal for healing in many tissues. The two characteristics were achieved by a new fabrication process combining phase separation and sphere templating. The resulting scaffolds are non-cytotoxic according to the ISO 10993-5 standard. In addition, the three-dimensional culture of microglial cells within the scaffolds demonstrates cell attachment and maintenance of a rounded, quiescent morphology, potentially due to spatial confinement. These results justify further in vivo studies and suggest broad potential in CNS applications, such as brain-computer interfaces, neural regeneration, and basic neurobiology. Subject classification codes: Neural Interfaces, soft hydrogel, synthetic biomaterials