Ms. Maureen Newman, a PhD Graduate Student in the Department of Biomedical Engineering at the University of Rochester and a Senior contributor to BioNews Texas, recently attended the TERMIS-AM meeting in Washington, DC. During her participation in the meeting, she reported on the keynote address, which was delivered by Rice University’s Dr. Antonios Mikos.
“Our laboratory for the past 23 years has been interested in new biomaterials,” began Dr. Antonios Mikos of Rice University at the 2014 Tissue Engineering and Regenerative Medicine International Society-Americas (TERMIS-AM) Meeting. Speaking on Saturday morning during the first keynote, Dr. Mikos, a past president of TERMIS, began the first day of scientific sessions with an overview of his work in the field of scaffolds for tissue engineering applications.
By mentoring over 90 graduate students and post-doctoral fellows throughout the years, Dr. Mikos has contributed greatly to the world of biomedical engineering. “Over the years, we and other have shown that by controlling structure, we can direct the development of new tissues,” said Dr. Mikos. During his talk, entitled “Biomaterials for Tissue Engineering,” Dr. Mikos highlighted the subjects of scaffolds for cell culture and transplantation, conduits for guided tissue growth, substrates for targeted cell adhesion, stimulates for desired cellular response, non-viral vectors for gene delivery, carriers for controlled drug delivery, and space maintainers of tissue defects.
To begin, Dr. Mikos described how extracellular matrix (ECM) greatly influences cell behavior and how it plays a major role in scaffolds for tissue engineering. Scaffolds can range from macro-scale–such as 3D printed scaffolds containing uniform and gradient pore architectures, created using open-source printing techniques–to micro/nano-scale. “There have been significant advances in the field of tissue engineering with nano-materials,” explained Dr. Mikos. “We and other have shown over the years that nano-materials can elicit exciting biomaterial properties we try to harness for tissue engineering matrices.”
For the past 20 years, Dr. Mikos’ group has used flow-perfusion bioreactors to make tissue engineering constructs to be used for 3D cell culture and transplantation or as platforms for discovery. His group has tried to use the same principles and the same technology of tissue engineering to create 3D models of tumors. When using these platforms, the group discovered that anticancer drugs act extremely different when applied in a 3D setting due to diffusion and biochemical/biomechanical signals. These models have thus proven to be important platforms for screening different drugs.
In addition to pre-formed scaffolds for drug delivery, injectable growth factor carriers have been studied in the Mikos group. Specifically, carriers containing different compositions of biomolecules and cells have been used to heal damage to bone and cartilage in osteochondral defects. This year, the group published the work “Dual Growth Factor Delivery from Bilayered, Biodegradable Hydrogel Composites for Spatially-Guided Osteochondral Tissue Repair.” The group used oligo(poly(ethylene glycol) fumarate) (OPF) as carriers of insulin-like growth factor-1 (IGF1) and BMP2 to influence chondrogenesis and osteogenesis. One key finding of the study was an interplay, or communication, of the two layers of tissue in the process of osteochondral healing. IGF1 within the chondral layer affected the subchondral layer, and BMP2 within the subchondral layer affected the chondral layer, but only when delivered together, indicating that one layer cannot be engineered independently of the other.
Along the same lines of osteochondral repair, Dr. Mikos used biomaterials to encapsulate pre-differentiated mesenchymal stem cells (MSCs) in this year’s publication, “Osteochondral Defect Repair Using Bilayered Hydrogels Encapsulating Both Chondrogenically and Osteogenically Pre-Differentiated Mesenchymal Stem Cells in a Rabbit Model.” The same OPF biomaterial was used in this study, and rabbits were treated with a variety of cell combinations. At the conclusion of the study, the team discovered that MSC pre-differentiation prior to implantation enhanced healing, and optimizing chondrogenic differentiation could greatly impact the quality of healing. “We asked basic questions to develop new biomaterials and exciting platforms to answer advanced questions and develop constructs to engineer tissue,” said Dr. Mikos.
Shifting gears, Dr. Mikos also described how non-viral gene delivery can be achieved through biomaterials. He touched upon how his lab has shown poly(ethylenimine)-hyaluronic acid (PEI-HA) is an excellent carrier to use for non-viral gene delivery. Dr. Mikos discussed how, in the 2010 paper “Regulated Non-Viral Gene Delivery from Coaxial Electrospun Fiber Mesh Scaffolds,” his group synthesized electrospun PEI-HA scaffolds containing plasmid DNA in the core and induced green fluorescent protein (GFP) expression in fibroblasts. The team is also applying the system to induce chrogenesis using the transcription factors RUNX2 and the SOX trio (SOX5, 6, and 9).
Another exciting application of biomaterials Dr. Mikos discussed is thermoresponsiveness. Certain polymers, such as poly(N-isopropylacrylamide) (PNIPAAm), with a lower critical solution temperature (LSCT) around body temperature can be used to deliver drugs in a controlled way. At the LCST, there is a hydrophilic/hydrophobic switch that can be exploited to release drugs. Alternatively, as was discussed at the conference and in another publication out this year (“Synthesis and Characterization of Injectable, Biodegradable, Phosphate-Containing, Chemically Cross-Linkable, Thermoresponsive Macromers for Bone Tissue Engineering“), PNIPAAm scaffolds can be used to create hydrogels that instantly solidify upon injection into the body. These hydrogels were applied to the context of bone tissue engineering, as they induce innate mineralization outside of added factors. An added benefit of these thermogelling macromers is their enzymatic degradability. The phosphate groups allow for breakdown of the construct through hydrolysis and alkaline phosphatase activity.
Another aspect of Dr. Mikos’ group is a relationship with the Armed Forces Institute of Regenerative Medicine “to accelerate regenerative solutions for the treatment of battlefield injuries.” The collaboration is currently aiming to treat composite defects in craniofacial areas and highly contaminated wounds. Until recently, how regeneration and infection affect each other and the overall healing process has not been addressed.
An application in the works that will be translated into the clinic is regeneration of hard bone tissue with soft tissue. The team is using space maintainers to release antibiotics and regrow soft tissue in a region of infection during bone repair. An inert biomaterial intended to be removed after soft tissue regrowth is the basis of the technique. “To address these issues, a novel composite material comprising poly(propylene fumarate) (PPF) with N-vinyl pyrrolidone (NVP) as the crosslinking agent, carboxymethylcellulose (CMC) hydrogel as a porogen, and antibiotic loaded poly(lactic-co-glycolic acid) (PLGA) microparticles as antibiotic carriers and porogen was fabricated,” wrote the group in a publication from this year, entitled “Degradable, Antibiotic Releasing Poly(propylene fumarate)-based Constructs for Craniofacial Space Maintenance Applications.” The group has used in vivo studies in rabbits for three years to investigate healing of a bicortical defect in mandibles with both soft tissue injury and oral cavity access. These studies led to the development of biomaterials that will eventually be translated to clinical use.
At the close of Dr. Mikos’ keynote, a question from the audience inquired about the prospect of curing osteoarthritis simply by injecting subchondral bone with growth factors to stimulate chondral tissue regrowth. Keeping with the nature of the scientific process, Dr. Mikos indicated that this hypothesis would need to be tested, but also that there is definitely interplay between the two layers. Perhaps one day, in addition to the astounding number of awards, recognitions, and honors already held by Dr. Mikos, “Curer of Osteoarthritis” may be added to the list.