Regenerative medicine technologies rely heavily on the use of well‐designed biomaterials for therapeutic applications. The success of implantable biomaterials hinges upon the ability of the chosen ...biomaterial to negotiate with the biological barriers in vivo. The most significant of these barriers is the immune system, which is composed of a highly coordinated organization of cells that induce an inflammatory response to the implanted biomaterial. Biomimetic platforms have emerged as novel strategies that aim to use the principle of biomimicry as a means of immunomodulation. This principle has manifested itself in the form of biomimetic scaffolds that imitate the composition and structure of biological cells and tissues. Recent work in this area has demonstrated the promising potential these technologies hold in overcoming the barrier of the immune system and, thereby, improve their overall therapeutic efficacy. In this review, a broad overview of the use of these strategies across several diseases and future avenues of research utilizing these platforms is provided.
Tissue engineering has focused on the development of therapeutic strategies that combine materials, stem cells, and biomolecules for the following goal: complete tissue regeneration. However, the immune response to these biomaterials challenges the successful implementation of these technologies. This review highlights emerging biomimetic approaches in biomaterial design that target and modulate the inflammatory environment in order to mediate tissue restoration.
A major challenge in regenerative medicine is to improve therapeutic cells' delivery and targeting using an efficient and simple protocol. Mesenchymal stem cells (MSC) are currently employed for the ...treatment of inflammatory-based diseases, due to their powerful immunosoppressive potential. Here we report a simple and versatile method to transiently overexpress the hyaluronic acid (HA) receptor, CD44, on MSC membranes, to improve their homing potential towards an inflammatory site without affecting their behavior. The effect of HA-coatings on murine MSC was functionally determined both, in vitro and in vivo as a consequence of the transient CD44 overexpression induced by HA. Data obtained from the in vitro migration assay demonstrated a two-fold increase in the migratory potential of HA-treated MSC compared to untreated cells. In an LPS-induced inflamed ear murine model, HA-treated MSC demonstrated a significantly higher inflammatory targeting as observed at 72 hrs as compared to untreated cells. This increased accumulation for HA-treated MSC yielded a substantial reduction in inflammation as demonstrated by the decrease in the expression of pro-inflammatory markers and by the induction of a pro-regenerative environment.
Focal chondral lesions of the knee are the most frequent type of trauma in younger patients and are associated with a high risk of developing early posttraumatic osteoarthritis. The only current ...clinical solutions include microfracture, osteochondral grafting, and autologous chondrocyte implantation. Cartilage tissue engineering based on biomimetic scaffolds has become an appealing strategy to repair cartilage defects. Here, a chondrogenic collagen‐chondroitin sulfate scaffold is tested in an orthotopic Lapine in vivo model to understand the beneficial effects of the immunomodulatory biomaterial on the full chondral defect. Using a combination of noninvasive imaging techniques, histological and whole transcriptome analysis, the scaffolds are shown to enhance the formation of cartilaginous tissue and suppression of host cartilage degeneration, while also supporting tissue integration and increased tissue regeneration over a 12 weeks recovery period. The results presented suggest that biomimetic materials could be a clinical solution for cartilage tissue repair, due to their ability to modulate the immune environment in favor of regenerative processes and suppression of cartilage degeneration.
A biomimetic immune tuning scaffold is implanted in a full‐thickness chondral defect in rabbits. The early inflammatory infiltrates changed in the treated animals resulting in a better cartilage homeostasis at longer timepoints. This work represents the first approach of tuning the inflammatory reaction with a bulk material to achieve a better regeneration in cartilage.
Musculoskeletal reconstruction is an ongoing challenge for surgeons as it is required for one out of five patients undergoing surgery. In the past three decades, through the close collaboration ...between clinicians and basic scientists, several regenerative strategies have been proposed. These have emerged from interdisciplinary approaches that bridge tissue engineering with material science, physiology, and cell biology. The paradigm behind tissue engineering is to achieve regeneration and functional recovery using stem cells, bioactive molecules, or supporting materials. Although plenty of preclinical solutions for bone and cartilage have been presented, only a few platforms have been able to move from the bench to the bedside. In this review, we highlight the limitations of musculoskeletal regeneration and summarize the most relevant acellular tissue engineering approaches. We focus on the strategies that could be most effectively translate in clinical practice and reflect on contemporary and cutting‐edge regenerative strategies in surgery. Stem Cells Translational Medicine 2017;6:2186–2196
The schematic summarizes the architecture of the extracellular matrix (ECM) of bone and cartilage of a long bone. Bone tissue consists mostly of ECM composed of type I collagen, proteoglycans, and hydroxyapatite. Bone marrow is a spongy tissue present in the hollow spaces of bones and consist mainly of hematopoietic, stem, immune, and adipose cells. Articular cartilage is composed of a dense ECM principally composed of collagen (type II mostly), and proteoglycans.
In mammals, tissue regeneration is accomplished through a well-regulated, complex cascade of events. The disruption of the cellular and molecular processes involved in tissue healing might lead to ...scar formation. Most tissue engineering approaches have tried to improve the regenerative outcome following an injury, through the combination of biocompatible materials, stem cells and bioactive factors. However, implanted materials can cause further healing impairments due to the persistent inflammatory stimuli that trigger the onset of chronic inflammation. Here, it is described at the molecular, cellular and tissue level, the body response to a functionalized biomimetic collagen scaffold. The grafting of chondroitin sulfate on the surface of the scaffold is able to induce a pro-regenerative environment at the site of a subcutaneous implant. The early in situ recruitment, and sustained local retention of anti-inflammatory macrophages significantly reduced the pro-inflammatory environment and triggered a different healing cascade, ultimately leading to collagen fibril re-organization, blood vessel formation, and scaffold integration with the surrounding native tissue.
Background:
Bone marrow aspirate (BMA) is a common source for harvesting mesenchymal stem cells (MSCs), other progenitor cells, and associated cytokines and growth factors to be used in the biologic ...treatment of various orthopaedic pathologies. The aspirate is commonly centrifuged into a concentrated volume that can be immediately administered to a patient using commercially available kits. However, the handling and efficacy of BMA concentrate (BMAC) are still controversial.
Purpose:
To characterize BMA versus BMAC for MSC quantity, potency, and cytokine profile.
Study Design:
Controlled laboratory study.
Methods:
From 8 participants (age, 17-68 years), 30 mL of bone marrow was aspirated by a single surgeon from either the proximal humerus or distal femur and was separated into 2 equal samples. One sample was kept as BMA, and the other half was centrifuged into BMAC. The 2 samples then underwent flow cytometry for detection of MSCs, cell analysis for colony-forming units (CFUs), and cytokine profiling. A 2-tailed t test was used to detect differences between MSCs, CFUs, and cytokine density concentrations between BMA and BMAC.
Results:
The average concentration of MSCs in both BMA and BMAC was 0.001%. Average MSC events detected by flow cytometry were significantly higher in BMA versus BMAC (15.1 and 8.1, respectively; P < .045). Expanded MSCs demonstrated similar phenotypes, but CFUs were significantly increased in BMA compared with BMAC (104 vs 68 CFUs, respectively; P < .001). Total protein concentration and cytokine profiling demonstrated great variability between BMA and BMAC and between patients. Most importantly, BMAC failed to concentrate MSCs in 6 of 8 samples.
Conclusion:
There is great variability in MSC concentration, total protein concentration, and cytokine profile between BMA and BMAC.
Clinical Relevance:
When studying the clinical efficacy of BMAC, one must also evaluate the sample itself to determine the presence, concentration, and potency of MSCs if this is to be considered a cell-based therapy. Further standard operating procedures need to be investigated to ensure reproducible results and appropriate treatments.
Regenerative medicine has gained much attention and has been a hot topic in all medical fields since its inception, and dentistry is no exception. However, innovations and developments in basic ...research are sometimes disconnected from daily clinical practice. This existing gap between basic research and clinical practice can only be addressed with improved communication between clinicians, academicians, industry, and researchers to facilitate the advance of evidence-based therapies and procedures and to direct research to areas of clinical need. In this perspective, six participants with strong clinical and research interests debated five previously conceived questions. These questions covered current methods and procedures for soft and hard tissue regeneration in the oral cavity with predictable outcomes, limitations of their respective protocols, and needs for future development of regenerative materials and technologies.
Atrial fibrillation induced stroke accounts for up to 15% of all strokes. These strokes are caused approximately 90% of the time by clot formation in the left atrial appendage (LAA). To prevent these ...clots, the most common approach is to administer blood thinners. However, contraindications prevent some people from being able to have blood thinners. Devices have been developed to seal the LAA to prevent clot formation in these patients. Current devices, such as the LARIAT® tie off the LAA theoretically preventing blood from entering the LAA. These have had limited clinical success mainly due to failure to completely close the LAA leaving holes and orifices for thrombi to form. To overcome this lack of complete closure, many surgeons use off-label approaches, classically filling the LAA filamentous coils, to cover these holes. Although this usually helps largely cover the holes, placement is challenging, the coils can migrate, the holes are not fully closed as there is space within and around the coils that don't fully mold to the LAA geometry. Furthermore, the coils can develop device related thrombi defeating their purpose. Therefore, these are not fully sufficient to complement the closure techniques in closing the LAA. To address limitation of the closure devices and coil sealing of remaining holes, we developed a thermally responsive hydrogel (Thermogel) that solidifies once injected into the LAA to uniformly and fully close off the LAA thus preventing clot formation and device related thrombi. This Thermogel consists of three portions: 1) a structural component composed of thiolated Pluronic F127 for gel to solid transition following injection, 2) Heparin for anticoagulation, and 3) Dopamine for adhesion to the surrounding endothelium in the turbulent flow encountered in cardiovascular applications. Here we have demonstrated that Thermogel, in conjunction with the LARIAT®, is capable of filling the defects in small and large animals through catheter injection. Thermogel was biocompatible and led to atrophy of the LAA at 5 weeks in a large animal model. Given the advantages of this Thermogel for sealing this defect and ability to be delivered through an endovascular approach, Thermogel presents a viable adjuvant to current occlusion-based treatments for sealing cardiovascular defects.
Visual Abstract: Thermally Responsive Hydrogel capable of injection into LAA. Display omitted
One Sentence Summary: We developed a thermally responsive hydrogel, termed Thermogel, capable of being injected to seal the left atrial appendage for prevention of atrial fibrillation related stroke.
Cartilage Repair
In article number 2101127 by Lewis W. Francis, Francesca Taraballi, and co‐workers, a biomimetic immune tuning scaffold is implanted in a full‐thickness chondral defect in rabbits. ...The early inflammatory infiltrates changed in the treated animals resulting in a better cartilage homeostasis at longer timepoints. This work represents the first approach of tuning the inflammatory reaction with a bulk material to achieve a better regeneration in cartilage.
Clinical trials have demonstrated that heparan sulfate (HS) could be used as a therapeutic agent for the treatment of inflammatory diseases. Its anti-inflammatory effect makes it suitable for the ...development of biomimetic innovative strategies aiming at modulating stem cells behavior toward a pro-regenerative phenotype in case of injury or inflammation. Here, we propose collagen type I meshes fabricated by solvent casting and further crosslinked with HS (HS-Col) to create a biomimetic environment resembling the extracellular matrix of soft tissue. HS-Col meshes were tested for their capability to provide physical support to stem cells' growth, maintain their phenotypes and immunosuppressive potential following inflammation. HS-Col effect on stem cells was investigated in standard conditions as well as in an inflammatory environment recapitulated
through a mix of pro-inflammatory cytokines (tumor necrosis factor-α and interferon-gamma; 20 ng/ml). A significant increase in the production of molecules associated with immunosuppression was demonstrated in response to the material and when cells were grown in presence of pro-inflammatory stimuli, compared to bare collagen membranes (Col), leading to a greater inhibitory potential when mesenchymal stem cells were exposed to stimulated peripheral blood mononuclear cells. Our data suggest that the presence of HS is able to activate the molecular machinery responsible for the release of anti-inflammatory cytokines, potentially leading to a faster resolution of inflammation.
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