Nikita Kalashnikov

Common polymeric surgical biomaterials are susceptible to dysregulated fibrous encapsulation, which contributes to failure in 10% of implantable medical devices. While biomaterial factors influencing the underlying foreign body response have been extensively studied, the role of the implantation site—specifically the tissue microenvironment—remains poorly understood. Here, we explore the tissue‐specificity of the foreign body response by evaluating fibrous encapsulation around clinically‐relevant synthetic non‐biodegradable polymers across distinct tissue microenvironments. We first characterize the physicochemical properties of PDMS, PP, PTFE, HDPE and nylon, and develop a mouse model that enables direct within‐animal comparisons of fibrous capsule formation next to skin, bone, fat, fascia and muscle. Using this model and these biomaterials, we histologically assess the extent and quality of fibrous encapsulation at 7 and 28 days for all biomaterial‐tissue combinations. At 7 days, capsules adjacent to muscle are the thickest, but—at 28 days—capsules in contact with bone and fascia reach comparable thicknesses, which are significantly greater than those of capsules adjacent to skin. Although PTFE and nylon elicit less fibrous encapsulation at 28 days than some of the other biomaterials, adjacent tissue type has a substantially greater influence on fibrous encapsulation than stiffness, roughness or wettability. Interestingly, more vascularized tissues (i.e., skin and muscle) do not show significant differences in capsule thickness over time, suggesting that they may promote a more rapid initiation and stabilization of the foreign body response. Together, these findings identify adjacent tissue type as a dominant predictor of fibrous encapsulation for common polymeric surgical biomaterials.

Implantable medical devices improve quality of life and reduce mortality by restoring the form and function of the human body. Their biomaterial surface components in contact with tissues are, however, susceptible to the host's foreign body response, which drives inflammation and implant fibrous encapsulation. When dysregulated, this response causes implant‐related patient morbidity and device failure, ultimately requiring revision surgery. Here, we review the roles that the biomaterial, the host, and the implantation surgery play in the foreign body response. Taking commonly‐used implantable medical devices as examples, we first describe the foreign body response; then, we examine the factors influencing it, and finally, we propose ideas of how it can be controlled perioperatively in an attempt to minimize implant‐related complications.

Using viscoelastically-tunable polyacrylamide hydrogels, we show that macrophage morphology and phagocytosis depend on substrate loss modulus, indicating that viscoelasticity may be an important design parameter in immunomodulatory biomaterials.

Innate immunity forms the core of the human body's defense system against infection, injury, and foreign objects. It aims to maintain homeostasis by promoting inflammation and then initiating tissue repair, but it can also lead to disease when dysregulated. Although innate immune cells respond to their physical microenvironment and carry out intrinsically mechanical actions such as migration and phagocytosis, we still do not have a complete biophysical description of innate immunity. Here, we review how engineering tools can be used to study innate immune cell biophysics. We first provide an overview of innate immunity from a biophysical perspective, review the biophysical factors that affect the innate immune system, and then explore innate immune cell biophysics in the context of migration, phagocytosis, and phenotype polarization. Throughout the review, we highlight how physical microenvironments can be designed to probe the innate immune system, discuss how biophysical insight gained from these studies can be used to generate a more comprehensive description of innate immunity, and briefly comment on how this insight could be used to develop mechanical immune biomarkers and immunomodulatory therapies.

Cell-generated forces play a foundational role in tissue dynamics and homeostasis and are critically important in several biological processes, including cell migration, wound healing, morphogenesis, and cancer metastasis. Quantifying such forces in vivo is technically challenging and requires novel strategies that capture mechanical information across molecular, cellular, and tissue length scales, while allowing these studies to be performed in physiologically realistic biological models. Advanced biomaterials can be designed to non-destructively measure these stresses in vitro, and here, we review mechanical characterizations and force-sensing biomaterial-based technologies to provide insight into the mechanical nature of tissue processes. We specifically and uniquely focus on the use of these techniques to identify characteristics of cell and tissue “tensegrity:” the hierarchical and modular interplay between tension and compression that provide biological tissues with remarkable mechanical properties and behaviors. Based on these observed patterns, we highlight and discuss the emerging role of tensegrity at multiple length scales in tissue dynamics from homeostasis, to morphogenesis, to pathological dysfunction.

Standard high-throughput screening (HTS) assays rarely identify clinically viable ‘hits’, likely because cells do not experience physiologically realistic culture conditions. The biophysical nature...

The placental syncytiotrophoblast is a giant multinucleated cell that forms a tree-like structure and regulates transport between mother and baby during development. It is maintained throughout pregnancy by continuous fusion of trophoblast cells, and disruptions in fusion are associated with considerable adverse health effects including diseases such as preeclampsia. Developing predictive control over cell fusion in culture models is hence of critical importance in placental drug discovery and transport studies; but this can currently be only partially achieved with biochemical factors. Here, we investigate whether biophysical signals associated with budding morphogenesis during development of the placental villous tree can synergistically direct and enhance cultured trophoblast fusion. We use micropatterning techniques to manipulate physical stresses in engineered microtissues, and demonstrate that biomimetic geometries simulating budding robustly enhances fusion and alter spatial patterns of synthesis of pregnancy-related hormones. These findings indicate that biophysical signals play a previously unrecognized and significant role in regulating placental fusion and function, in synergy with established soluble signals. More broadly, our studies demonstrate that biomimetic strategies focusing on tissue mechanics can be important approaches to design, build, and test placental tissue cultures for future studies of pregnancy-related drug safety, efficacy and discovery.

Fibrous tissue gap closure is a critically important process initiated in response to traumatic injury. Recent three-dimensional (3D) bioengineered models capture cellular details of this process, including wound retraction and closure, but have high failure rates, are labor-intensive, and require considerable expertise to develop and implement with tools that are typically not available in standard wet laboratories. Here, we develop a simple and effective 3D-printed wounding platform to reliably create and puncture arrays of prestressed tissues and monitor subsequent wound dynamics. We demonstrate the ability to create a range of wound sizes in a contractile collagen/fibroblast tissue, within 125 μm of the desired target location, with high degrees of circularity. Wounds exhibit an initial expansion due to tissue prestress, and sufficiently small wounds close completely within 24 h, while larger wounds initially closed much more rapidly, but did not complete the closure process. Simulating the dynamics of tissue retraction with a viscoplastic finite element model indicates a temporary elevation of circumferential stresses around the wound edge. Finally, to determine whether active wounding and retraction of the tissue significantly affect closure rates, we compared active puncture of prestressed tissue with passive removal of a structure that prevents closure, and found that active wounding and retraction substantially accelerated wound closure when compared with the passive case. Taken together, our findings support the role of active tissue mechanics in wound closure arising from an initial retraction of the tissue. More broadly, these findings demonstrate the utility of the platform and methodology developed here in further understanding the mechanobiological basis for wound closure. Impact Statement: In vitro models to study wound formation and closure in prestressed tissue are typically challenging to implement. This work provides an easily accessible approach to produce and analyze wounds in arrays of contractile tissues that recapitulate critical features of wound retraction and closure in animal models. The specific modeling and experiments results presented here suggest that mechanobiology effects arising from wound retraction in viscoplastic extracellular matrices could play an important role in driving wound closure.

Manipulating the shape of preformed living tissues can present a novel fabrication route toward complex biological architectures. However, external manipulation of tissues can be challenging to implement robustly at multiple length scales and with high degrees of freedom, particularly in soft fibrous tissue constructs. Here, a versatile platform is developed to drive soft tissue morphodynamics using embeddable shape memory actuators that generate multiscale, repetitive, and highly customized tissue deformation on demand. To achieve this, a thermally isolating coating technique is designed and developed for programmable shape memory wires, which protects surrounding biological materials from cytotoxic heating effects during wire actuation. The coated tissue actuators (CTAs) can then be embedded in engineered tissues and activated to produce both large‐ and small‐scale tissue deformations in a highly customized and reproducible manner. Using this strategy, tissues can be forced to adopt specified shapes, with precise control over cell elongation and orientation within an encapsulating matrix. Furthermore, the system can produce predictable, highly localized, and customizable strains within fibrous matrices, capable of elongating cells and biasing their orientation within degrees of a desired direction. This strategy may hence have broad applicability in both applied tissue biofabrication and for fundamental studies of cell–matrix interactions.