Advancing biomaterials of human origin for tissue engineering

Tissue engineering has emerged as a new treatment approach for bone repair and regeneration seeking to address limitations associated with current therapies, such as autologous bone grafting. While many bone tissue engineering approaches have traditionally focused on synthetic materials (such as polymers or hydrogels), there has been a lot of excitement surrounding the use of natural materials due to their biologically inspired properties. Fibrin is a natural scaffold formed following tissue injury that initiates hemostasis and provides the initial matrix useful for cell adhesion, migration, proliferation, and differentiation. Fibrin has captured the interest of bone tissue engineers due to its excellent biocompatibility, controllable biodegradability, and ability to deliver cells and biomolecules. Fibrin is particularly appealing because its precursors, fibrinogen, and thrombin, which can be derived from the patient's own blood, enable the fabrication of completely autologous scaffolds. In this article, we highlight the unique properties of fibrin as a scaffolding material to treat bone defects. Moreover, we emphasize its role in bone tissue engineering nanocomposites where approaches further emulate the natural nanostructured features of bone when using fibrin and other nanomaterials. We also review the preparation methods of fibrin glue and then discuss a wide range of fibrin applications in bone tissue engineering. These include the delivery of cells and/or biomolecules to a defect site, distributing cells, and/or growth factors throughout other pre-formed scaffolds and enhancing the physical as well as biological properties of other biomaterials. Thoughts on the future direction of fibrin research for bone tissue engineering are also presented. In the future, the development of fibrin precursors as recombinant proteins will solve problems associated with using multiple or single-donor fibrin glue, and the combination of nanomaterials that allow for the incorporation of biomolecules with fibrin will significantly improve the efficacy of fibrin for numerous bone tissue engineering applications.

/pdf/a-review-of-fibrin-and-fibrin-composites-for-bone-tissue-57be4mczwd.pdf

A review of fibrin and fibrin composites for bone tissue engineering

Decellularized tissue and cell-derived extracellular matrices as scaffolds for orthopaedic tissue engineering.

Given their highly porous nature and excellent water retention, hydrogel-based biomaterials can mimic critical properties of the native cellular environment. However, their potential to emulate the electromechanical milieu of native tissues or conform well with the curved topology of human organs needs to be further explored to address a broad range of physiological demands of the body. In this regard, the incorporation of nanomaterials within hydrogels has shown great promise, as a simple one-step approach, to generate multifunctional scaffolds with previously unattainable biological, mechanical, and electrical properties. Here, recent advances in the fabrication and application of nanocomposite hydrogels in tissue engineering applications are described, with specific attention toward skeletal and electroactive tissues, such as cardiac, nerve, bone, cartilage, and skeletal muscle. Additionally, some potential uses of nanoreinforced hydrogels within the emerging disciplines of cyborganics, bionics, and soft biorobotics are highlighted.

Nanoreinforced Hydrogels for Tissue Engineering: Biomaterials that are Compatible with Load-Bearing and Electroactive Tissues.

Mesenchymal stem cell (MSC)-based therapies are under broad investigation for applications in tissue repair but suffer from poor cell persistence and engraftment upon transplantation. MSC spheroids exhibit improved survival, anti-inflammatory, and angiogenic potential in vitro, while also promoting vascularization when implanted in vivo. However, these benefits are lost once cells engage the tissue extracellular matrix and migrate from the aggregate. The efficacy of cell therapy is consistently improved when using engineered materials, motivating the need to investigate the role of biomaterials to instruct spheroid function. In order to assess the contribution of adhesivity on spheroid activity in engineered materials and promote the bone-forming potential of MSCs, we compared the function of MSC spheroids when entrapped in Arg-Gly-Asp (RGD)-modified alginate hydrogels to nonfouling unmodified alginate. Regardless of material, MSC spheroids exhibited reduced caspase activity and greater vascular endothelial growth factor (VEGF) secretion compared with equal numbers of dissociated cells. MSC spheroids in RGD-modified hydrogels demonstrated significantly greater cell survival than spheroids in unmodified alginate. After 5 days in culture, spheroids in RGD-modified gels had similar levels of apoptosis, but more than a twofold increase in VEGF secretion compared with spheroids in unmodified gels. All gels contained mineralized tissue 8 weeks after subcutaneous implantation, and cells entrapped in RGD-modified alginate exhibited greater mineralization versus cells in unmodified gels. Immunohistochemistry confirmed more diffuse osteocalcin staining in gels containing spheroids compared with dissociated controls. This study demonstrates the promise of cell-instructive biomaterials to direct survival and function of MSC spheroids for bone tissue engineering applications.

Significance
Mesenchymal stem cell (MSC) spheroids exhibit improved therapeutic potential in vitro compared with dissociated MSCs, yet spheroids are directly injected into tissues, ceding control of cell function to the extracellular matrix and potentially limiting the duration of improvement. Cell delivery using adhesive biomaterials promotes cell retention and function. These studies explored the role of adhesion to the surrounding matrix on spheroid function. When entrapped in an adhesive biomaterial, MSC spheroids exhibited improved survival and proangiogenic growth factor secretion in vitro and bone formation in vivo compared with cells in nonadhesive hydrogels. These findings demonstrate the value of deploying MSC spheroids in instructive biomaterials to improve cell function.

/pdf/increased-survival-and-function-of-mesenchymal-stem-cell-4plu5zjlfv.pdf

Increased Survival and Function of Mesenchymal Stem Cell Spheroids Entrapped in Instructive Alginate Hydrogels

Alginate hydrogels containing cell-instructive cues are the subject of intense interest for their use as cell carriers in bone tissue engineering. Peptides and proteins are chemically grafted onto these hydrophilic materials to facilitate adhesion and direct phenotype of entrapped cells. However, the presentation of a single or small number of peptides does not represent the complexity of the native extracellular matrix (ECM) of bony tissues. Mesenchymal stem cells (MSCs) secrete ECM that can be harvested and deposited on various substrata to promote osteogenic differentiation. In this study, we hypothesized that the presentation of engineered cell-secreted ECM on microbeads suspended in alginate hydrogels would promote cell adhesion and enhance osteogenic differentiation of undifferentiated MSCs without chemical incorporation of cell-adhesive peptides. Human MSCs entrapped in alginate hydrogels loaded with ECM-coated beads showed increased interaction with beads, when compared with cells suspended in hyd...

Alginate hydrogels containing cell-interactive beads for bone formation

Fibrin gels are a promising material for use in promoting bone repair and regeneration due to their ease of implant formation, tailorability, biocompatibility, and degradation by natural processes. However, these materials lack necessary osteoconductivity to nucleate calcium, integrate with surrounding bone, and promote bone formation. Polymeric substrata formed from poly(lactide-co-glycolide) (PLG) are widely used in bone tissue engineering. A carbonated apatite layer of bone-like mineral can be successfully grown on the surface of PLG microspheres after a multiday incubation process in modified simulated body fluid. Such coatings improve the osteoconductivity of the polymer, provide nucleation sites for cell-secreted calcium, and enhance the potential osseointegration with host tissue. We examined the capacity of mineralized polymeric microspheres suspended within fibrin hydrogels to enhance the osteoconductivity of fibrin gels and increase the osteogenic potential of these materials. The inclusion of microparticles, both nonmineralized and mineralized, reduced the capacity of mesenchymal stem cells (MSCs) to contract the gel. When cultured in osteogenic media, we detected a near linear increase in both calcium and phosphate incorporation in gels containing mineralized microspheres and entrapped MSCs. The osteoconductivity of acellular fibrin gels with mineralized and nonmineralized microspheres was assessed in a rodent calvarial bone defect over 12 weeks. Compared to untreated rodent calvarial bone defects, we detected significant increases in early vascularization when treated with fibrin gels, with greater vascularization, on average, occurring with gels containing microspheres. We detected a trend for increased bone mineral density in gels containing mineralized microspheres after 12 weeks. These findings demonstrate that the osteoconductivity of fibrin gels can be increased by inclusion of mineralized microspheres, but additional signals may be required to rapidly accelerate bone repair.

/pdf/enhancing-osteoconductivity-of-fibrin-gels-with-apatite-2dyhmucm7o.pdf

Enhancing Osteoconductivity of Fibrin Gels with Apatite-Coated Polymer Microspheres

We describe a case of a 56-year-old woman with systemic lupus erythematosus (SLE) who presented with breast mass, axillary lymphadenopathy, and renal mass. The breast lesion was diagnosed as infiltrating ductal carcinoma. However, the renal mass evaluation was suggestive of a primary lymphoma. Primary renal lymphoma (PRL) with breast cancer in an SLE patient has rarely been reported.

Primary renal lymphoma masquerading as metastasis in a patient with primary breast cancer and systemic lupus erythematosus.

Bone Tissue Engineering: Fabrication and Use of Electrospun Meshes

This case report presents the clinical details, investigations, diagnosis, treatment and outcomes of a male patient in his 50s who presented with weight loss and fatigue. On evaluation, he had axillary lymphadenopathy, along with hypercalcaemia and elevated serum creatinine levels. The patient was diagnosed with tuberculous lymphadenitis based on lymph node biopsy and positive tuberculosis (TB)-PCR results. Treatment involved hydration, salmon calcitonin and zoledronic acid, leading to symptomatic improvement. This case highlights the rarity of hypercalcaemia and renal dysfunction in TB and underscores the importance of considering this entity in the differential diagnosis.

Hypercalcaemia in a patient with tuberculous lymphadenitis

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