The rate at which nanotechnology and tissue engineering has seen innovations move from bench to bedside has been slower than expected. The demand for products with desired properties for clinical therapy (high targeting, low toxicity) and surgical applications (high biocompatibility, compliance with organ function) remains elevated. We recognized that the body has incredible healing capabilities and have worked to harness these to their fullest potential by creating biomimetic platforms able to mimic the cellular and molecular events that occur during the physiologic healing process and to elicit desired cell and tissue responses.

The Center for Musculoskeletal Regeneration is focused on the use of cutting edge nano- and bio-materials for drug delivery and tissue engineering. Our goal is to develop implantable and injectable platforms able to overcome relevant biological barriers, target inflammation, control the release of therapeutics, and tune immune response. Our efforts are directed towards the treatment of currently unmet traumatic and pathological conditions. By combining cell biology with nanotechnology, we create innovative medical technologies that work within, and not around, the laws of nature.

The Leukosome: Biomimetic Extracellular Vesicles

We developed a new class of biomimetic nanoparticles inspired by the ability of leukocytes to target inflammation and infiltrate inflamed tissues. By using the cell membrane proteins of leukocytes and other immune cells as building blocks, we created injectable nanoparticles able to avoid reticuloendothelial clearance, specifically target cancer vessels, cross the endothelial layer, and increase accumulation of therapeutic payloads in the cancer parenchyma.

Using the body's own molecular components, we built drug delivery systems camouflaged as, and with similar functions to, our own body's defense system. Leukosomes selectively target inflammation, the common denominator among a number of pathologies that affect humans including cancer, cardiovascular diseases, trauma, and infection. Our goal is to develop a universal delivery system to target inflammation, and release different types of drugs and bioactive molecules that are specific to the disease.

The Nanoneedles: Nanoporous Silicon for Cytoplasmic Delivery

Progress and impact in biotechnology is rooted in the ability to place large biomolecules — such as DNA, RNA and proteins — into living cells to modulate their function. The gold standard method to access a cell’s interior is through the use of micropipettes. However, because micropipettes treat one cell at a time, they suffer from extremely low throughput. Viruses are able to efficiently introduce exogenous genetic material into cells and are extensively used in the laboratory setting, but safety concerns have limited their clinical translation. To solve this issue we used microfabrication tools to massively parallelize the nano-injection process so that millions of cells could be treated at once.

Porous nanoneedles are a first-in-class platform for the localized, intracellular delivery of therapeutic payloads. The system accounts for the cell’s biology in order to avoid toxicity and efficiently deliver nucleic acids through the avoidance of endolysosomal trafficking. By directly injecting siRNA/DNA in the cytoplasm of target cells, we demonstrated enhanced in vivo neovascularization after localized administration of a VEGF expression plasmid. As biological research and medical applications require increased access to the intracellular machinery that controls cellular function, the direct access that nanoneedles provide to the cytosol, nucleus, and possibly other compartments of the cell makes nanoneedle-mediated intracellular delivery a powerful approach.

Collagen scaffolds: an Acellular Approach to Musculoskeletal Regeneration

Our approach to biomaterials for tissue engineering is focused on studying the reactions of inflammatory cells such as macrophages, dendritic, and T cells, to biomaterials. We demonstrated that all regenerative processes are dependent on a complex dialogue between multiple cell types, also involving the chemical and physical cues provided by the surrounding microenvironment. We were among the first to characterize the cascade of inflammatory events triggered by the host’s immune system in response to an implanted biomaterial.

Macrophages are key players in this response. The activation of M1 macrophages leads to adverse immune dysfunction, fibrosis, and pathological complications. Conversely, M2 switching is associated with faster tissue healing and can prevent scar tissue formation. Through our studies, we showed that immune and stem cells respond to an implanted material according to its composition, structure, and surface properties. Our work in tissue engineering pioneered the synthesis of scaffolds and membranes that mimic native tissue at the nano- and micro-scale in order to bestow the function of natural tissues upon synthetic constructs. To augment implant biocompatibility and minimize immunogenic response, we developed several immune-instructive biomaterials able to tune the immune-response towards improved regeneration.

Environmentally Responsive Polymers: Exploring Unmet Surgical Needs

Through the development of clinically and physiologically relevant animal models, we have bridged the gap between current materials used in human surgery, and future interventions able to enhance the healing of human defects and injuries. We have applied our expertise in drug delivery to surgical analgesia using preclinical models of incisional pain. Using a lidocaine-based nanohydrogel formulation, we were able to diminish postoperative pain with equivalent efficacy to opioid narcotics. In collaboration with the Department of Cardiovascular Science, we also developed injectable polymers able to seal vascular and cardiac defects and are in the process of validating these materials in large preclinical animal models.

As a testimony to our translational research, we are also conducting the first large-scale FDA preclinical study to test the osteoregenerative capability of a novel biocompatible polymer system to mechanically stabilize and regenerate a critical-sized long bone defect without the assistance of any internal or external fixation.

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