This Small Business Innovation (SBIR) Phase I project will provide critical advances in the understanding of interactions between mesenchymal stem cells and a novel fibrin microthread suture construct in an effort to overcome significant inefficiencies in the field of cell therapy delivery. This work will develop a novel seeding vessel and associated regimen for highly efficient mesenchymal stem cell loading to be applied to fibrin microthread sutures. Once such a regimen has been developed, resultant devices will be implanted intramuscularly in a rat model to explore cell delivery efficiency and host response to the cell-loaded fibrin microthread device. The resultant cell seeding data will provide insight into the extent to which cell seeding efficiency in vitro may be manipulated by simplistic modifications to common seeding conditions including vessel geometry, cell concentration, and total cell load. The in vivo work will provide critical information describing the biocompatibility of fibrin microthreads, cell delivery efficiency of syringe-mediated compared to fibrin microthread-mediated interventions, and inflammatory/fibrotic potential of these interventions respectively. In turn, the systems developed in this project will be expected to provide a platform for further research of cell therapy performed with discreetly delivered, highly viable, and accurately dosed cell populations.
The broader impact/commercial potential of this project relates not only to the specific indication targeted, Achilles tendon, but more broadly to other connective tissue repairs, other enhanced healing indications, and other cell delivery applications. Once fully realized, the Achilles tendon repair augmentation market alone is projected to be worth $500M annually in the United States. While the suture-like form factor may not be ideal for all applications, several types of open surgeries performed upon poorly healing or non-healing organ systems could readily benefit from cell delivery by this technology. This would include indications such as myocardial infarct repair, neural tissue regeneration in cases of stroke, and cochlear tissue regeneration. The successful commercialization of our project represents a significant step forward in tissue engineering and next generation cell-based medicines, promising to improve both longevity and quality of life for countless people.
Normal 0 false false false EN-US X-NONE X-NONE This project sought to develop and demonstrate a highly efficient stem cell seeding system for use with a novel fibrin microthread suture which would improve the ease and efficiency of cell therapy delivery. It was hoped that a simplistic cell seeding system with could uniformly and efficiently seed fibrin microthread bundles with minimal user manipulation and high repeatability. Such a vessel might be used directly in the operating theatre, providing rapid turn-around on cell-seeded device. This was expected to build upon previous demonstrations of the suitability of fibrin microthread suture for highly efficient and localized stem cell delivery for regenerative medicine. This could significantly reduce cell therapy delivery inefficiencies, where current techniques deliver 1-10% of their cell payload to their intended target, wasting the vast majority and potentially causing complications elsewhere. Upon demonstrating proof of concept, future plans included application in dramatically reducing the 6-12 month recovery typically associated with the over 200,000 Achilles tendon repairs performed in the U.S. each year and improving patient outcomes. The first objective of this project was to develop a seeding system for the fibrin microthreads able to be used with minimal skill and handling time. A series of different vessel geometries and seeding conditions were trialed in an effort to identify a best set of conditions. High levels of cell binding were observed on the seeded fibrin microthreads, typically around 10-40% of applied payload. Performance of replicate experiments to confirm initial findings reinforced overall material and vessel performance trends, though they indicated substantial variability across replicates. Microscopic evaluation of the seeded fibrin microthreads revealed inconsistent circumferential and overall quantitative cell distribution. This is believed to have stemmed from a lack of cell and media agitation during seeding. While the use of a more complex cell seeding vessel might have overcome these issues, development of such a system would have been inconsistent with the aim of keeping the vessel as simple as possible. As an end result, this complicated subsequent study objectives. The second major objective of this project was intended to evaluate stem cell-seeded fibrin microthreads using a rat in vivo model skin incisional wound healing. Initial intent was to correlate cell load to both cell delivery efficiency and histologically observed tissue response. This was rendered impossible due to the variability of the stem cell seeding process employed. Successful cell delivery to the wound site was confirmed by visualizing at the incisional defect quantum dot-loaded cells which had been seeded on the fibrin microthreads. Following this, histological evaluation was performed on tissue which had received cell-loaded fibrin microthreads, acellular fibrin microthreads, or conventional suture treatment. Observations indicated that both cell-seeded and acellular fibrin microthreads behaved in a fashion which did not further inflame the local host tissue. While a likely outcome for cell-seeded devices based upon previous studies of stem cells and their known inflammation suppressing capabilities, the virtually non-existent host response and rapid absorption of the fibrin microthread suture was very unusual. The final objective of this project, unintended in the original research plan, was evaluation of the fibrin microthreads themselves as a stand-alone suture for incisional wound closure. Fibrin microthread sutures were compared against Vicryl again, using rat skin as a model. Gross observations indicated no difference between fibrin microthread sutures and Vicryl in their ability to close the incisional wounds. Both gross observations and histology demonstrated a similar healing time course for both the fibrin microthread sutures and the Vicryl. Most interestingly, the fibrin microthread sutures were bioresorbed within 2 weeks leaving behind no evidence, either cellular or deposited extracellular matrix materials, of their presence. Vicryl by comparison persisted out beyond 28 days and exhibited a mild but noted fibrotic encapsulation around the suture material. A suture made from fibrin microthreads could have tremendous value for plastic surgeries including blepharoplasty, rhinoplasty, face lifts, brow lifts, and other facial procedures performed on over 600,000 patients in the United States each year. Further, the fibrin microthreads could also potentially be infused with a pharmaceutical payload to enhance their effectiveness. For example, an active anti-scarring agent might provide a treatment for keloid scar prevention, a disease which affects hundreds of millions of people globally. While initial efforts at developing a simplistic, efficient, and highly reproducible seeding vessel were not entirely successful, a greater and more immediately relevant gain has been made in identifying the utility of fibrin microthreads as revolutionary suture material.
