Optimizing Skin-Implant Interface of Osseointegrated Device

Background: This work addresses research toward (a) osseointegration of upper extremity prostheses, including optimization of the skin-implant interface and (b) prevention of infection. Additionally, we address residual limb skin integrity and durability. We address the general issue of skin-to-implant attachment and healing for osseointegrated (OI) prostheses by focusing on integration and durability of their skin-to-implant interface that is microbially, mechanically, and biologically challenging. We focus on OI prosthetic implants anchored in the humerus that exit through the skin of residual upper extremities; however, our approach is also applicable to socket-based prostheses and those for other limbs. The reasoning behind our approach centers on improving skin adhesion and healing to the OI implant abutment as it exits the skin and improving the durability of this seal for long-term viability via infection, biofilm, and microbiome control. Our research idea is based on (a) recognizing the role of septal compartments that anchor tissue at the tips of appendages (finger, toe) and recapitulating these attachments with soft tissue scaffolds that create a strain gradient-protected transition zone surrounding the skin/implant interface and (b) exploiting existing human and mammalian settings where a hard tissue exits the body through the skin and targeting cells with the specialized function to flexibly adhere soft tissue to hard tissue.Objective/Hypothesis: The proposed strategy that will address our goals to optimize upper extremity OI implants with transdermal coupling is based on examining three hypotheses:Hypothesis 1: Septal scaffolds designed to limit tissue strain by providing gradual mechanical transition between hard implants and soft tissues will provide superior durability and sealing compared to sleeve scaffolds (with or without cells).Hypothesis 2: Cells with the normal physiologic function to adhere soft tissues to hard tissues will provide superior ex vivo and in vivo attachment to metal implant substrates and superior resistance to infection compared to normal epithelial cells.Hypothesis 3: Antimicrobial treatment of implant surfaces will improve sealing, durability, and resistance to skin infection.Specific Aims (SA) will test our hypotheses: SA1: Ex vivo: (a) Steer differentiation of human and swine MSC, iPS cells, and mature site-specific (gingival and hoof/nail bed) cells to adhesive/epithelial phenotypes and (b) characterize and rate ingrowth of these cells into scaffolds and their adhesive potential to metal substrates. SA2: In vivo: Test transdermal implants (a) with and without subdermal cellular augmentation in swine model, (b) with and without septal strain limiting scaffolds, and (c) under topical bacterial challenge.Study Design: Ex vivo cell identification, differentiation and scaffold seeding in SA1 will provide data to choose the optimal adhesive cells for in vivo evaluation. In SA2, an adaptive experimental design consisting of three cohorts of animals using an established swine model with multiple transdermal implants will allow efficient identification of the cell/scaffold construct with the best performance.Relevance: We based our approach on existing clinical work with OI implants; our strategy is to identify specific problems with currently available systems and to use basic science and our swine model to address these problems in a logical, step-wise approach. Our use of human cell types (including iPSC) has precedent in clinical trials. Swine skin models are highly relevant to represent structure and response of human skin. To maximize translational potential, we will use both swine and human cells to identify those that perform the best. Risk will be minimized by using candidate swine cells in swine model, and then using corresponding “best of best” human cells in the final cohort to provide data needed to use these human cells for human clinical trials in the US. Involvement of basic scientists with patented surface treatments and committed commercial partners is key. Surgical consultants, who are currently implanting and critically following OI prostheses in Denmark, further position our team for efficient and better-informed clinical transition to use in the military setting.