Advances in In Vitro and In Vivo Bioreactor-Based Bone Generation for Craniofacial Tissue Engineering

Craniofacial reconstruction requires robust bone of specified geometry for the repair to be both functional and aesthetic.While native bone from elsewhere in the body can be harvested,shaped,and implanted within a defect,using either an in vitro or in vivo bioreactors eliminates donor site morbidity while increasing the customizability of the generated tissue.In vitro bioreactors utilize cells harvested from the patient,a scaffold,and a device to increase mass transfer of nutrients,oxygen,and waste,allowing for generation of larger viable tissues.In vivo bioreactors utilize the patient’s own body as a source of cells and of nutrient transfer and involve the implantation of a scaffold with or without growth factors adjacent to vasculature,followed by the eventual transfer of vascularized,mineralized tissue to the defect site.Several different models of in vitro bioreactors exist,and several different implantation sites have been successfully utilized for in vivo tissue generation and defect repair in humans.In this review,we discuss the specifics of each bioreactor strategy,as well as the advantages and disadvantages of each and the future directions for the engineering of bony tissues for craniofacial defect repair.

Corrigendum to “Advances in In Vitro and In Vivo Bioreactor-Based Bone Generation for Craniofacial Tissue Engineering”

In the review article“Advances in In Vitro and In Vivo Bioreactor-Based Bone Generation for Craniofacial Tissue Engineering,”the authors made an error in Table.In Table,10 cells in the Results column contain the word“enter,”which was erroneously added instead of starting a new line of text during proofing.This error did not affect the results,discussion,or conclusion of this paper.Table 1 has now been corrected in the PDF and HTML(full text).

Tissue Engineering and Regulatory Science

Tissue engineering has successfully evolved from its original concept[1]into medical products with a rapid pace of develop-ment and a multi-billion dollar market[2].Compared with tradi-tional medical products,tissue-engineered medical products(TEMPs)have distinct characteristics that provide unique benefits for the repair and regeneration of damaged or diseased tissues or organs[1,2].

Machine Learning and Medical Devices:The Next Step for Tissue Engineering

The pathway for creating and seeing a medical device to market is time-intensive,costly,and demanding[1,2].This is particularly true of devices developed with tissue engineering components within the device[1,3].Machine learning and artificial intelligence have expedited optimization and engineering design in many other engineering disciplines[4,5].

A high-strength mineralized collagen bone scaffold for large-sized cranial bone defect repair in sheep

Large-sized cranial bone defect repair presents a great challenge in the clinic.The ideal cranioplasty materials to realize the functional and cosmetic recovery of the defect must have sufficient mechanical support,excellent biocompatibility,good osseointegration and biodegradability as well.In this study,a high-strength mineralized collagen(MC)bone scaffold was developed with biomimetic composition,microstructure and mechanical properties for the repair of sheep largesized cranial bone defects in comparison with two traditional cranioplasty materials,polymethyl methacrylate and titanium mesh.The compact MC scaffold showed no distinct pore structure and therefore possessed good mechanical properties.The strength and elastic modulus of the scaffold were much higher than those of natural cancellous bone and slightly lower than those of natural compact bone.In vitro cytocompatibility evaluation revealed that the human bone marrow mesenchymal stem cells(hBMSC)had good viability,attachment and proliferation on the compact MC scaffold indicating its excellent biocompatibility.An adult sheep cranial bone defect model was constructed to evaluate the performances of these cranioplasty materials in repairing the cranial bone defects.The results were investigated by gross observation,computed tomography scanning as well as histological assessments.The in vivo evaluations indicated that compact MC scaffold showed notable osteoconductivity and osseointegration with surrounding cranial bone tissues by promoting bone regeneration.Our results suggested that the compact MC scaffold has a promising potential for large-sized cranial bone defect repair.

Development of a modular, biocompatible thiolated gelatin microparticle platform for drug delivery and tissue engineering applications

The field of biomaterials has advanced significantly in the past decade.With the growing need for high-throughput manufacturing and screening,the need for modular materials that enable streamlined fabrication and analysis of tissue engineering and drug delivery schema has emerged.Microparticles are a powerful platform that have demonstrated promise in enabling these technologies without the need to modify a bulk scaffold.This building block paradigm of using microparticles within larger scaffolds to control cell ratios,growth factors and drug release holds promise.Gelatin microparticles(GMPs)are a well-established platform for cell,drug and growth factor delivery.One of the challenges in using GMPs though is the limited ability to modify the gelatin post-fabrication.In the present work,we hypothesized that by thiolating gelatin before microparticle formation,a versatile platform would be created that preserves the cytocompatibility of gelatin,while enabling post-fabrication modification.The thiols were not found to significantly impact the physicochemical properties of the microparticles.Moreover,the thiolated GMPs were demonstrated to be a biocompatible and robust platform for mesenchymal stem cell attachment.Additionally,the thiolated particles were able to be covalently modified with a maleimide-bearing fluorescent dye and a peptide,demonstrating their promise as a modular platform for tissue engineering and drug delivery applications.

A dual-gelling poly(N-isopropylacrylamide)-based ink and thermoreversible poloxamer support bath for high-resolution bioprinting

Extrusion bioprinting is a popular method for fabricating tissue engineering scaffolds because of its potential to rapidly produce complex,bioactive or cell-laden scaffolds.However,due to the relatively high viscosity required to maintain shape fidelity during printing,many extrusion-based inks lack the ability to achieve precise structures at scales lower than hundreds of micrometers.In this work,we present a novel poly(N-isopropylacrylamide)(PNIPAAm)-based ink and poloxamer support bath system that produces precise,multi-layered structures on the tens of micrometers scale.The support bath maintains the structure of the ink in a hydrated,heated environment ideal for cell culture,while the ink undergoes rapid thermogelation followed by a spontaneous covalent crosslinking reaction.Through the combination of the PNIPAAm-based ink and poloxamer bath,this system was able to produce hydrogel scaffolds with uniform fibers possessing diameters tunable from 80 to 200μm.A framework of relationships between several important printing factors involved in maintaining support and thermogelation was also elucidated.As a whole,this work demonstrates the ability to produce precise,acellular and cell-laden PNIPAAm-based scaffolds at high-resolution and contributes to the growing body of research surrounding the printability of extrusion-based bioinks with support baths.

Translation of biomaterials from bench to clinic

Scientific research originates from curiosity and interests. Translational research of biomaterials should always focus on addressing specific needs of the targeted clinical applications. The guest editors of this special issue hope that the included articles have provided cutting-edge biomaterials research as well as insights of the translation of biomaterials from bench to clinic.

Biomaterials and regulatory science

The fast development of both biomaterials and regulatory science calls for a convergence,which is addressed in this article via their link through medical products of biomaterials and related safety and efficacy evaluation.The updated definition of biomaterials,and concepts of biomaterials-related medical products and so-called medical-grade and implantable materials are firstly introduced.Then a brief overview of the concept and history of regulatory science and its assessment of safety and efficacy of medical products,as well as the currently ongoing biomaterials-related regulatory science programs are presented.Finally,the opportunities provided by regulatory science for biomaterials as well as challenges on how to develop a biomaterials-based regulatory science system are discussed.As the first article in the field to elucidate the relationship between biomaterials and regulatory science,key take-home messages include(1)biomaterials alone are not medical products;(2)regulatory authorities approve/clear final medical products,not biomaterials;(3)there is no definition/regulation on the so-called medical-grade or implantable materials;and(4)safety and efficacy refer to final medical products,not biomaterials alone.

Evaluating the physicochemical effects of conjugating peptides into thermogelling hydrogels for regenerative biomaterials applications

Thermogelling hydrogels,such as poly(N-isopropylacrylamide)[P(NiPAAm)],provide tunable constructs leveraged in many regenerative biomaterial applications.Recently,our lab developed the crosslinker poly(glycolic acid)-poly(ethylene glycol)-poly(glycolic acid)-di(but-2-yne-1,4-dithiol),which crosslinks P(NiPAAm-co-glycidyl methacrylate)via thiol-epoxy reaction and can be functionalized with azide-terminated peptides via alkyne-azide click chemistry.This study’s aim was to evaluate the impact of peptides on the physicochemical properties of the hydrogels.The physicochemical properties of the hydrogels including the lower critical solution temperature,crosslinking times,swelling,degradation,peptide release and cytocompatibility were evaluated.The gels bearing peptides increased equilibrium swelling indicating hydrophilicity of the hydrogel components.Comparable sol fractions were found for all groups,indicating that inclusion of peptides does not impact crosslinking.Moreover,the inclusion of a matrix metalloproteinase-sensitive peptide allowed elucidation of whether release of peptides from the network was driven by hydrolysis or enzymatic cleavage.The hydrophilicity of the network determined by the swelling behavior was demonstrated to be the most important factor in dictating hydrogel behavior over time.This study demonstrates the importance of characterizing the impact of additives on the physicochemical properties of hydrogels.These characteristics are key in determining design considerations for future in vitro and in vivo studies for tissue regeneration.

Important Topics in the Future of Tissue Engineering

Over 150 participants from around the world congregated on the beautiful island of Kos—home of Hippocrates,Father of Medicine—from June 20 to June 25,2014,to share their research findings and engage in dialogue pertaining to progress in tissue engineering.Since the field’s inception,we have witnessed its astonishing development over the past 30 years and the groundbreaking work stemming from both laboratory and clinical settings.Despite continuously evolving concepts and strategies,the essential ingredients of scaffolds,cells and growth factors remain to be explored further.