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Cell-based therapies have emerged as promising approaches for regenerative medicine. Hydrophobic poly(ester urethane)s offer the advantages of robust mechanical properties, cell attachment without the use of peptides, and controlled degradation by oxidative and hydrolytic mechanisms. However, the application of injectable hydrophobic polymers to cell delivery is limited by the challenges of protecting cells from reaction products and creating a macroporous architecture post-cure. We designed injectable carriers for cell delivery derived from reactive, hydrophobic polyisocyanate and polyester triol precursors. To overcome cell death caused by reaction products from in situ polymerization, we encapsulated bone marrow-derived stem cells (BMSCs) in fastdegrading, oxidized alginate beads prior to mixing with the hydrophobic precursors. Cells survived the polymerization at >70% viability, and rapid dissolution of oxidized alginate beads after the scaffold cured created interconnected macropores that facilitated cellular adhesion to the scaffold in vitro. Applying this injectable system to deliver BMSCs to rat excisional skin wounds showed that the scaffolds supported survival of transplanted cells and infiltration of host cells, which improved new tissue formation compared to both implanted, pre-formed scaffolds seeded with cells and acellular controls. Our design is the first to enable injectable delivery of settable, hydrophobic scaffolds where cell encapsulation provides a mechanism for both temporary cytoprotection during polymerization and rapid formation of macropores post-polymerization. This simple approach provides potential advantages for cell delivery relative to hydrogel technologies, which have weaker mechanical properties and require incorporation of peptides to achieve cell adhesion and degradability.
Copyright © 2015 Elsevier Ltd. All rights reserved.
Remarkable achievements have been made in the clinical application of mechanical circulatory support and cardiac transplantation for patients with end-stage heart failure. Despite the successes, complications associated with these therapies continue to drive cardiac regenerative research utilizing stem cell based therapies. Multiple stem cell lineages hold clinical promise for cardiac regeneration-mostly through cellular differentiation, cellular fusion, and paracrine signaling mechanisms. Bone marrow-derived endothelial progenitor cells are among the most intriguing and controversial cell types currently being investigated. Formidable barriers exist, however, in finding the ideal cardiac regenerative stem cell, such as identifying specific lineage markers, optimizing in vitro cellular expansion and improving methods of stem cell delivery. Hybrid approaches of cardiac regeneration using stem cell therapies in conjunction with immunomodulation after cardiac transplantation or with mechanical circulatory support produce cutting edge stem cell technologies. This review summarizes the current knowledge and therapeutic applications of stem cells in patients with end-stage heart failure, including stem cell therapy after implantation of mechanical circulatory support and cardiac transplantation.
© 2014 Wiley Periodicals, Inc.
Inflammation and angiogenesis are inevitable in vivo responses to biomaterial implants. Continuous progress has been made in biomaterial design to improve tissue interactions with an implant by either reducing inflammation or promoting angiogenesis. However, it has become increasingly clear that the physiological processes of inflammation and angiogenesis are interconnected through various molecular mechanisms. Hence, there is an unmet need for engineering functional tissues by simultaneous activation of pro-angiogenic and anti-inflammatory responses to biomaterial implants. In this work, the modulus and fibrinogen adsorption of porous scaffolds were tuned to meet the requirements (i.e., ~100 kPa and ~10 nm, respectively), for soft tissue regeneration by employing tyrosine-derived combinatorial polymers with polyethylene glycol crosslinkers. Two types of functional peptides (i.e., pro-angiogenic laminin-derived C16 and anti-inflammatory thymosin β4-derived Ac-SDKP) were loaded in porous scaffolds through collagen gel embedding so that peptides were released in a controlled fashion, mimicking degradation of the extracellular matrix. The results from (1) in vitro coculture of human umbilical vein endothelial cells and human blood-derived macrophages and (2) in vivo subcutaneous implantation revealed the directly proportional relationship between angiogenic activities (i.e., tubulogenesis and perfusion capacity) and inflammatory activities (i.e., phagocytosis and F4/80 expression) upon treatment with either type of peptide. Interestingly, cotreatment with both types of peptides upregulated the angiogenic responses, while downregulating the inflammatory responses. Also, anti-inflammatory Ac-SDKP peptides reduced production of pro-inflammatory cytokines (i.e., interleukin [IL]-1β, IL-6, IL-8, and tumor necrosis factor alpha) even when treated in combination with pro-angiogenic C16 peptides. In addition to independent regulation of angiogenesis and inflammation, this study suggests a promising approach to improve soft tissue regeneration (e.g., blood vessel and heart muscle) when inflammatory diseases (e.g., ischemic tissue fibrosis and atherosclerosis) limit the regeneration process.
Craniofacial injuries can result from trauma, tumor ablation, or infection and may require multiple surgical revisions. To address the challenges associated with treating craniofacial bone defects, an ideal material should have the ability to fit complex defects (i.e. be conformable), provide temporary protection to the brain until the bone heals, and enhance tissue regeneration with the delivery of biologics. In this study, we evaluated the ability of injectable lysine-derived polyurethane (PUR)/allograft biocomposites to promote bone healing in critical-size rabbit calvarial defects. The biocomposites exhibited favorable injectability, characterized by a low yield stress to initiate flow of the material and a high initial viscosity to minimize the adverse phenomena of extravasation and filter pressing. After injection, the materials cured within 10-12 min to form a tough, elastomeric solid that maintained mechanical integrity during the healing process. When injected into a critical-size calvarial defect in rabbits, the biocomposites supported ingrowth of new bone. The addition of 80 µg mL(-1) recombinant human bone morphogenetic protein-2 (rhBMP-2) enhanced new bone formation in the interior of the defect, as well as bridging of the defect with new bone. These observations suggest that injectable reactive PUR/allograft biocomposites are a promising approach for healing calvarial defects by providing both mechanical stability as well as local delivery of rhBMP-2.
OBJECTIVE - To determine if a dual-purpose bone graft can regenerate bone and reduce infection in highly contaminated bone critical size defects in rats.
METHODS - Biodegradable polyurethane (PUR) scaffolds were loaded with recombinant human bone morphogenetic protein-2 (BMP-2) and vancomycin (Vanc). The release kinetics of the BMP-2 were tuned to take advantage of its mechanism of action (ie, an initial burst to recruit cells and sustained release to induce differentiation of the migrating cells). The Vanc release kinetics were designed to protect the graft from contamination until it is vascularized by having a burst for a week and remaining well over the minimum inhibitory concentration for Staphylococcus aureus for 2 months. The bone regeneration and infection reduction capability of these dual-purpose grafts (PUR+Vanc+BMP-2) were compared with collagen sponges loaded with BMP-2 (collagen+BMP-2) and PUR+BMP-2 in infected critical size rat femoral segmental defects.
RESULTS - The dual-delivery approach resulted in substantially more new bone formation and a modest improvement in infection than PUR+BMP-2 and collagen+BMP-2 treatments.
CONCLUSIONS - The PUR bone graft is injectable, provides a more sustained release of BMP-2 than the collagen sponge, and can release antibiotics for more than 8 weeks. Thus, the dual-delivery approach may improve patient outcomes of open fractures by protecting the osteoinductive graft from colonization until vascularization occurs. In addition, the more optimal release kinetics of BMP-2 may reduce nonunions and the amount of growth factor required.
OBJECTIVES/HYPOTHESIS - To test urinary bladder matrix (UBM) as a potential treatment for tympanic membrane (TM) healing and regeneration.
STUDY DESIGN - This prospective pilot study was designed to provide both qualitative and semiquantitative assessment of temporal and spatial healing events in the chinchilla model of chronic TM perforations with and without UBM patching.
METHODS - Bilateral myringotomies were performed and repeated as necessary to create subtotal perforations over an 8-week period. Myringoplasty was then performed, with left TMs serving as controls and right TMs receiving UBM patches. TMs were excised at 4 weeks, 8 weeks, and 12 weeks. Fixed tissue samples were characterized for gross morphology, then processed for microscopic evaluation.
RESULTS - Chronic perforations were maintained with one or more repeated myringotomies. Although both control and patched TMs were thicker than native tissue, patched TMs were transparent and uniform in thickness without any inclusions. UBM patches were readily degraded and replaced by newly deposited and organized host tissue that recapitulated the native TM layers.
CONCLUSIONS - UBM scaffolds were an effective biological scaffold for TM closure and tissue remodeling, leading to thicker than normal anatomy but otherwise normal morphology. Future studies are required to determine functional and temporal outcomes as well as alternative patch orientations. The results show particular promise as a superior alternative means of reconstructing not only chronic TM perforations but also dimeric TMs associated with retraction pockets and atelectasis. Laryngoscope, 2009.
Porous biomaterials designed to support cellular infiltration and tissue formation play a critical role in implant fixation and engineered tissue repair. The purpose of this Leading Opinion Paper is to advocate the use of high resolution 3D imaging techniques as a tool to quantify extracellular matrix formation and vascular ingrowth within porous biomaterials and objectively compare different strategies for functional tissue regeneration. An initial over-reliance on qualitative evaluation methods may have contributed to the false perception that developing effective tissue engineering technologies would be relatively straightforward. Moreover, the lack of comparative studies with quantitative metrics in challenging pre-clinical models has made it difficult to determine which of the many available strategies to invest in or use clinically for companies and clinicians, respectively. This paper will specifically illustrate the use of microcomputed tomography (micro-CT) imaging with and without contrast agents to nondestructively quantify the formation of bone, cartilage, and vasculature within porous biomaterials.