Design of Biomaterials toward Endogenous Skeletal Tissue Repair

Abstract

<p>Repair of skeletal tissues remains a significant challenge in patient care as there is high incidence of impaired fracture healing as well as irreversible cartilage degeneration following joint injury. To improve the repair outcome, recent advancements have been made in regenerative medicine involving administration of tissue-specific growth factors and transplantation of stem cells. While they have achieved some success, their broad clinical application is hindered by various challenges, notably high costs and safety concerns. Alternatively, strategies that enable innate repair mechanisms without cell or protein products may hold great potential for tissue repair. In this dissertation, I explore biomaterials that are low-risk, cost-effective, and capable of leveraging endogenous healing mechanisms to promote skeletal tissue health. </p><p>Adenosine, a nucleoside ubiquitously present in the human body, is a potent pro-healing small molecule. A surge in adenosine secretion ensuing from injury is integral to the natural repair mechanisms. There is growing evidence that harnessing adenosine signaling can be a powerful therapeutic strategy. However, the needed abundance of adenosine often does not persist throughout the healing process due to the fast clearance or imbalanced bone homeostasis. Herein, I describe a synthetic biomaterial containing boronate molecules that sequesters adenosine reversibly and sustains the pro-regenerative signaling locally at the injury site. I demonstrate that implantation of the biomaterial post-fracture establishes an in-situ stockpile of adenosine, resulting in accelerated healing by promoting both osteoblastogenesis and angiogenesis. This biomaterial-assisted approach can leverage the transient increase in extracellular adenosine following injury to present adenosine to cells in a temporal manner. In addition to sequestering endogenous adenosine, the biomaterial is able to deliver exogenous adenosine to the site of injury, offering a versatile solution to utilizing adenosine as a potential therapeutic for tissue repair. Given the wide distribution of adenosine in the body, this biomaterial system can have a significant impact on a wide range of diseases by modulating local adenosine signaling, thus advancing its clinical applications beyond bone health.</p><p>Hyaluronic acid is a key component in synovial fluid that protects cartilage and facilitates painless motion. Loss of hyaluronic acid after joint trauma disrupts the native protection mechanism and contributes to the deterioration of cartilage and subsequent osteoarthritis. Although replenishing native hyaluronic acid with viscosupplementation is commonly used in clinics, its therapeutic efficacy is largely inconsistent at least in part due to the short joint retention. To enhance the longevity and chondroprotective function of hyaluronic acid supplementation, I report a design of self-healing supramolecular biomaterial by incorporating dynamic physical crosslinking into hyaluronic acid. Consequently, the supramolecular biomaterial exhibits unique shear-thinning by reshuffling the crosslinking in response to mechanical force, resulting in improved injectability and lubrication. Furthermore, the supramolecular biomaterial is rapidly reconstructed in the absence of force, forming a stable, crosslinked network. Using a murine model of anterior cruciate ligament injury, I confirm that the supramolecular biomaterial minimizes cartilage damage with an extended joint residence in comparison with the unmodified hyaluronic acid. Therefore, the introduction of physical crosslinking to create such a self-healing biomaterial can serve as an effective solution to chondroprotection.</p><p>Together, this dissertation offers two novel biomaterial systems to support bone and cartilage health. They are developed to capture the potential of endogenous healing mechanisms, highlighting a new paradigm of biomaterial engineering for regenerative medicine.</p>