Researchers are learning more about the mechanisms of cell-scaffold interactions and tissue development. This knowledge has provided the groundwork for synthesizing sophisticated scaffolds that are able to both provide more complex biological signals to the nascent tissue and respond specifically to the biological environment. Materials that can respond to cell behavior and their biological environment are described as intelligent or bioresponsive materials.
Multifunctional hydrogels. Synthetic hydrogels such as those derived from PEG have gained significant attention in the research community as vehicles for 3D cell culture. They have also been translated and tested in a select number of clinical applications. Unfortunately PEG does not have any functional sites for modification after a hydrogel is formed. To address this challenge we generated PEG hydrogels that are “decorated” with cyclodextrin (CD), similar to beads on a necklace. There are multiple functional groups on the CD molecules that can then be manipulated to incorporate desired functionality and the materials can also serve as a tool to independently control scaffold mechanics and adhesion or other functionality. We are generating a variety of these materials and applying to a number of biological problems including evaluation of cancer cell growth.
Fiber-reinforced hydrogels. The native extracellular matrix (ECM) includes not only a hydrogel (proteoglycan) portion but also a fiber (proteinacious) component. Electrospinning is a frequently utilized technique to form nano-sized fibers that can mimic the fiber component of the ECM. We are creating nanofiber scaffolds using electrospinning that contain biological molecules and fibers that contain ECM-derived signals. Furthermore, in collaboration with Hai Quan Mao we are incorporating small molecule signals into the fibers to direct cell function.
Integration of the Synthetic and Biological World. Numerous barriers exist when applying technologies developed in vitro to the in vivo environment. For example, while investigators have been able to engineer cartilage, integration of the newly generated cartilage with surrounding native tissue in vivo remains a significant problem since cartilage has a dense, avascular extracellular matrix that impedes cell migration and healing. We are examining techniques to bond our synthetic materials to cartilage and soft tissues for integration of engineered cartilage and as a tissue adhesive for would repair.
Clinical Tools. Surrounded by Hopkins physicians, we are often presented with surgical challenges and unique problems that are faced by our colleagues in clinical cases. Working together with clinical collaborators we design biomaterials-based solutions to address clinical challenges where current options are limited or inefficient.
Both adult and embryonic stem cells have demonstrated significant potential in regenerative medicine, however there is still much to learn about how these cells can be used to repair and regenerative tissues. Research is needed to both understand basic mechanisms of stem cell behavior and how these cells can be leveraged therapeutically.
Basic stem cell research in the laboratory focuses on applying biomaterials to understand mechanisms of stem cell behavior. For example, new materials that allow independent control over functionalization, adhesion, and mechanical properties can be used to probe stem cell function and differentiation capacities. We are also comparing adult and embryonic stem cell abilities to secrete stimulatory molecules to promote differentiation and repair versus directly forming new tissues. Finally, we are integrating cutting edge fields such as synthetic biology to stem cell research.
Biological signals are often required to promote cell differentiation and tissue formation. Growth factors are traditional biological signals that have been employed to promote tissue development and can be incorporated in biomaterials and tissue engineering systems. We are investigating new potential small molecule biological signals to promote tissue repair. In collaboration Kevin Yarema we are testing new synthetic sugar analogs that impact cell behavior including modulating aspects of inflammation. In addition, we are probing metabolic activities of cells and how these pathways can be manipulated to stimulate tissue growth.
Cartilage tissue was one of the initial targets for tissue repair in the lab. We studied cartilage tissue growth in hydrogel materials to understand basic cell-material interactions and developed enabling technologies to translate the tissue engineering approaches. One hydrogel technology was translated to clinical testing via a startup (Cartilix, acquired by Biomet in 2009) and continues development. As a result of that clinical translation we realized the complexity of joint disease and are now pursuing a multi-targeted approach to the problem that includes lubrication and inflammation in addition to structural repair.
To address structural tissue repair in orthopedic tissues we are developing next generation biomaterial technologies based on our first clinical experience with cartilage repair. Specifically, we have simplified the surgical procedure for implantation of our materials, created a one step implant process with a new biosynthetic hydrogel. We are developing new materials that can work with intra-operative biologics (bone marrow, platelets, etc) and composite materials.
Inflammation is another critical aspect in joint disease. Inflammation can occur after trauma (even surgical trauma) and disease processes and will impact tissue repair. To address the challenge of inflammation in the joint we partnered with the Yarema Lab that generated a new molecule based on short chain fatty acid hexosamines. Some of these molecules reduce expression of inflammatory markers such as those found in osteoarthritic cells. Furthermore, new cartilage production is increased in the OA cells treated with the new small molecules that reduce inflammation. As these small molecules are not protein growth factors we expect a simpler translation process to testing in the joint and more efficient delivery.
Finally, we have looked at improving lubrication in the joint. Currently, injections of hyaluronic acid into the joint are quite popular clinically. HA is purported to be a lubricant but is not retained in the joint for very long. Taking cues from other industries such as the auto industry where engine surfaces are designed to interact with engine oil, we developed a technology to modify the cartilage surface to interact specifically with HA to retain the molecule in the joint long term. This technology is also biomimetic in that it replicates the natural function of lubricin in the joint.
Taken together, addressing these three research areas will provide a comprehensive approach to solve the complex clinical challenge of joint dysfunction.
With the recent move to the Wilmer Eye Institute Smith Building collaborations with ophthalmology and ocular tissue engineering have expanded. The collaborative EyePatch project with the JHU Applied Research Lab (APL) investigates the application of biomaterials to corneal reconstruction with special emphasis on war-related injuries. This project utilizes a biosynthetic ocular adhesive and new biological membranes to stimulate repair. We are also investigating methods to leverage stem cells, biomaterials, and tissue-derived scaffolds to regenerate corneal endothelium. Leveraging our materials background, we are designing new devices for application in both the front and back of the eye.