Editorial Cite This: ACS Biomater. Sci. Eng. 2018, 4, 1113−1114
Regenerative Biomaterials
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inflammatory disease. They designed microspheres comprised of poly(propylene sulfate) (PPS), which scavenges ROS and undergoes a phase transition from hydrophobic to hydrophilic upon oxidation. Injection of the PPS microspheres enhanced revascularization in a murine hindlimb ischemia model and mitigated articular cartilage damage in a post-traumatic osteoarthritis model. In addition to ROS, neutrophils also secrete chemokines that recruit monocytes, which then clear apoptotic neutrophils to continue the wound healing process. Like neutrophils, monocytes are heterogeneous, and exist in the bloodstream in at least two different states, one pro-inflammatory and the other anti-inflammatory. To leverage the fact that antiinflammatory monocytes express higher levels of the receptors for the chemoattractant factors stromal-derived factor 1-alpha (SDF1a) and FTY720, Ogle and colleagues5 designed hydrogels that released these two factors using a dually functional affinity-based controlled release system. Sustained release of SDF1a from the PEG-DA-based hydrogels was achieved through affinity with heparin, while the lipid FTY720 was released from affinity interactions with albumin. Implantation of the dual factor-releasing hydrogels into partial thickness skin wounds in mice resulted in enhanced recruitment of antiinflammatory monocytes compared to hydrogels that released either factor alone. The monocytes differentiated into proreparative macrophages and enhanced vascularization, a key part of wound healing. In further appreciation of the importance of macrophages for angiogenesis and wound healing, Graney et al. 6 provide a thorough review of macrophages and biomaterial design strategies to control them. Even more so than neutrophils and monocytes, macrophages are known for their ability to dynamically shift phenotypes between extremes, with properties ranging from pro-inflammatory to anti-inflammatory and pro-fibrotic to matrix-degrading, depending on the situation. In particular, the importance of timing is highlighted, as macrophages with diverse phenotypes are required at different stages of tissue repair and regeneration. Therefore, biomaterials that control the presentation of diverse biochemical cues to macrophages in a temporally controlled manner are likely to achieve greater success. A major process controlled by macrophages is angiogenesis, orchestrated by endothelial cells and support cells like pericytes. Although the biochemical cues that influence this process have been studied for decades, the effects of biophysical cues are only recently becoming appreciated. Zohar et al.7 show that shear stress induced by fluid flow through tissue-engineered blood vessel networks in porous polymeric scaffolds enhances vessel maturation, stability, and interactions with fibroblasts. These findings will be critical for engineering 3D tissues that are stable following implantation into the body.
he goal of regenerative medicine is to coax the body into regenerating tissues in order to restore function to damaged body parts. The cells and signaling pathways involved in this complex process are highly interconnected and multifaceted. How does one design biomaterials to facilitate tissue regeneration in such a complex system? First, it is helpful to understand the major cells, signaling pathways, and matrix molecules that are involved, and how biomaterials can be designed to modulate each one. In this special issue, the contributors take you through each major player, highlighting biomaterial design parameters that can be leveraged to manipulate them. Of course, each component affects another, so the ultimate regenerative biomaterial will need to take all of these processes into consideration. Sekhon and colleagues1 begin the issue with a review of platelets, the first cells to respond to an injury. The unique surface structure of platelets allows them to bind to the site of injury and to each other, forming a platelet plug that arrests bleeding. In addition to this essential function, they are also critical cells for stimulating the wound healing cascade through the release of cytokines and growth factors from their granules. As a result, platelet-derived treatments like platelet-rich plasma (PRP) have been explored in a plethora of applications, with mixed outcomes. Precisely controlled biomaterials that harness the stimulating capacity of platelets, including platelet-mimetic microparticles and scaffolds that deliver platelet secretomes, hold the potential to bypass the variability that plagues treatments based on direct platelet infusions. Jhunjunwala2 next highlights the first nucleated cell to arrive on the scene. Neutrophils are critical if poorly understood cells that are recruited by injured cells to sites of injury and biomaterial implantation. These short-lived cells are often maligned for their release of reactive oxygen species (ROS) that can cause collateral damage to surrounding tissue. However, with the understanding that neutrophils possess potent antiinflammatory propertiesunder the right conditionsopportunities emerge for biomaterials to exploit their immunomodulatory properties. Witherel et al.3 take a first step toward the design of neutrophil-modulating biomaterials in a primary research article describing host-biomaterial interactions in zebrafish. These genetically tractable and optically transparent model organisms allow up close-and-personal investigations into how cells respond to biomaterials in real time. The team showed that a typical foreign body response proceeds in response to implantation of a model biomaterial, polypropylene sutures; that phagocytosis of polystyrene microparticles is inversely proportional to microparticle diameter; and that controlled release of the immunomodulatory cytokine interleukin-10 attenuates recruitment of neutrophils but not macrophages to the site of injury. This system should allow many future high-throughput investigations into neutrophilbiomaterial interactions. Bypassing the neutrophils themselves and going straight to their major effector molecule, O’Grady and colleagues4 target the damaging effects of pathologically elevated levels of ROS in © 2018 American Chemical Society
Special Issue: Regenerative Biomaterials Received: March 23, 2018 Published: April 9, 2018 1113
DOI: 10.1021/acsbiomaterials.8b00358 ACS Biomater. Sci. Eng. 2018, 4, 1113−1114
ACS Biomaterials Science & Engineering
Editorial
In addition to supporting angiogenesis, fibroblasts are better known for their role in depositing extracellular matrix (ECM) that is critical for the closure of wounds and the restoration of tissue function. Hannan and colleagues8 review this surprisingly complicated cell type, which has no universal marker and thus is difficult to track in vivo. This point is particularly problematic considering that other cell types that are not typically considered fibroblasts can behave like them, contributing in major ways to fibrosis. Indeed, the fibrous capsule that forms around some biomaterials, isolating them from surrounding tissue and preventing their regenerative potential, is a collaboration between macrophages and fibroblasts. Mihalko and Brown9 shed light on this story by reviewing how many cell types undergo an epithelial-to-mesenchymal transition (EMT), taking on fibroblast-like properties in a process that is critical for tissue repair but that can result in fibrosis and cancer if left unchecked. They describe how the interactions between soluble factors, ECM binding, and biophysical cues from implanted biomaterials all contribute to modulate the EMT. The key to designing biomaterials to modulate EMT will be harnessing and carefully controlling its beneficial effects. Considering the importance of the ECM for tissue repair and regeneration, it is logical to design biomaterials that contain as much of the natural ECM as possible, as reviewed by Gaffney et al.10 ECM-derived scaffolds can be prepared by decellularization of a multitude of different tissues such that they largely retain each tissue’s specific bioactive and biophysical properties. Such scaffolds can give regenerating tissues a head start on the process of laying down new matrix. In particular, the team describes the utility of ECM-derived scaffolds to support the delivery and differentiation of stem cells, which is required for true regeneration of any tissue. Leach and Whitehead11 expand on this topic, reviewing biomaterial strategies to support differentiation of mesenchymal stem cells (MSCs) for the regeneration of bone, cartilage, muscle, and adipose tissues. These are very different tissues with very different biomaterial requirements for MSC differentiation. Wobma and colleagues12 extend the discussion of biomaterial-based delivery of MSCs to focus on the paracrine effects of these cells, which have been used in over 800 clinical trials over the past decade to treat various pathologies primarily through interactions with other cell types (especially those highlighted in the other articles of this special issue). Finally, Kiani and colleagues13 bring our attention to an intriguing model organ to study regenerative medicine, the hair follicle, which is one of only two structures that degenerates and regenerates in the adult. The hair follicle and its constituent cells have been used in clinical trials ranging from tendinosis to chronic ulcers. The authors first review the structure of this miniature organ, including its populations of stem cells, then move on to its modulation of skin regeneration. The authors then turn to the use of specific stem cell populations within the hair follicle to induce skin regeneration, as well as the isolation of keratin from hair fibers to provide material for regenerative scaffolds. This contribution in particular illustrates the creative strategy of working with the body’s natural systems to design novel approaches in regenerative medicine. Clearly, tissue regeneration is complex, involving a multitude of cell types and processes that must be coordinated for the restoration of tissue function. However, as the articles in this special issue clearly demonstrate, biomaterials can be designed to address all of them. Thorough understanding of how biomaterials modulate each aspect of tissue regeneration will be
critical to the design of next-generation regenerative biomaterials that can modulate multiple cells and processes to result in true restoration of tissue function.
Kara L. Spiller, Guest Editor
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School of Biomedical Engineering, Science, and Health Systems, Drexel University
AUTHOR INFORMATION
ORCID
Kara L. Spiller: 0000-0001-7798-1490 Notes
Views expressed in this editorial are those of the author and not necessarily the views of the ACS.
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REFERENCES
(1) Sekhon, U. D. S.; Sen Gupta, A. Platelets and Platelet-Inspired Biomaterials Technologies in Wound Healing Applications. ACS Biomater. Sci. Eng. 20184 (4), 10.1021/acsbiomaterials.7b00013. (2) Jhunjhunwala, S. Neutrophils at the Biological−Material Interface. ACS Biomater. Sci. Eng. 20184 (4), 10.1021/acsbiomaterials.6b00743. (3) Witherel, C. E.; Gurevich, D.; Collin, J. D.; Martin, P.; Spiller, K. L. Host−Biomaterial Interactions in Zebrafish. ACS Biomater. Sci. Eng. 20184 (4), 10.1021/acsbiomaterials.6b00760. (4) O’Grady, K. P.; Kavanaugh, T. E.; Cho, H.; Ye, H.; Gupta, M. K.; Madonna, M. C.; Lee, J.; O’Brien, C. M.; Skala, M. C.; Hasty, K. A.; Duvall, C. L. Drug-Free ROS Sponge Polymeric Microspheres Reduce Tissue Damage from Ischemic and Mechanical Injury. ACS Biomater. Sci. Eng. 20184 (4), 10.1021/acsbiomaterials.6b00804. (5) Ogle, M. E.; Krieger, J. R.; Tellier, L. E.; McFaline-Figueroa, J.; Temenoff, J. S.; Botchwey, E. A. Dual Affinity Heparin-Based Hydrogels Achieve Pro-Regenerative Immunomodulation and Microvascular Remodeling. ACS Biomater. Sci. Eng. 20184 (4), 10.1021/ acsbiomaterials.6b00706. (6) Graney, P. L.; Lurier, E. B.; Spiller, K. L. Biomaterials and Bioactive Factor Delivery Systems for the Control of Macrophage Activation in Regenerative Medicine. ACS Biomater. Sci. Eng. 20184 (4), 10.1021/acsbiomaterials.6b00747. (7) Zohar, B.; Blinder, Y.; Mooney, D. J.; Levenberg, S.Flow-Induced Vascular Network Formation and Maturation in Three- Dimensional Engineered Tissue. ACS Biomater. Sci. Eng. 2018, 4 (4), 10.1021/ acsbiomaterials.7b00025. (8) Hannan, R. T.; Peirce, S. M.; Barker, T. H. Fibroblasts: Diverse Cells Critical to Biomaterials Integration. ACS Biomater. Sci. Eng. 20184 (4), 10.1021/acsbiomaterials.7b00244. (9) Mihalko, E. P.; Brown, A. C. Material Strategies for Modulating Epithelial to Mesenchymal Transitions. ACS Biomater. Sci. Eng. 20184 (4), 10.1021/acsbiomaterials.6b00751. (10) Gaffney, L.; Wrona, E. A.; Freytes, D. O. Potential Synergistic Effects of Stem Cells and Extracellular Matrix Scaffolds. ACS Biomater. Sci. Eng. 20184 (4), 10.1021/acsbiomaterials.7b00083. (11) Leach, J. K.; Whitehead, J. Materials-Directed Differentiation of Mesenchymal Stem Cells for Tissue Engineering and Regeneration. ACS Biomater. Sci. Eng. 20184 (4), 10.1021/acsbiomaterials.6b00741. (12) Wobma, H. M.; Liu, D.; Vunjak-Novakovic, G. Paracrine Effects of Mesenchymal Stromal Cells Cultured in Three-Dimensional Settings on Tissue Repair. ACS Biomater. Sci. Eng. 20184 (4), 10.1021/acsbiomaterials.7b00005. (13) Kiani, M. T.; Higgins, C. A.; Almquist, B. D. The Hair Follicle: An Underutilized Source of Cells and Materials for Regenerative Medicine. ACS Biomater. Sci. Eng. 20184 (4), 10.1021/acsbiomaterials.7b00072.
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DOI: 10.1021/acsbiomaterials.8b00358 ACS Biomater. Sci. Eng. 2018, 4, 1113−1114
