Implantable Therapeutic Reservoir Systems for Diverse Clinical Applications in Large Animal Models

Duffy, Garry P.; Robinson, Scott T.; O'Connor, Raymond G.; Wylie, Robert B.; Mauerhofer, Ciaran; Bellavia, Gabriella; Straino, Stefania; Cianfarani, Francesca; Mendez, Keegan; Beatty, Rachel; Levey, Ruth E.; O’Sullivan, Janice; McDonough, Liam; Kelly, Helena; Roche, Ellen T.

doi:10.1002/adhm.202000305

Cited by 15 publications

(17 citation statements)

References 52 publications

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“…This novel macroencapsulation device not only improved tissue integration and peri-implant vascularity but also has shown to be retrievable and refillable, which is an important consideration for regulatory purposes [17]. We have previously demonstrated the ability to scale these devices for large animal models, while still allowing low profile, minimally invasive delivery, aligned to common interventional procedures [17,64].…”

Section: Discussionmentioning

confidence: 99%

Assessing the Effects of VEGF Releasing Microspheres on the Angiogenic and Foreign Body Response to a 3D Printed Silicone-Based Macroencapsulation Device

et al. 2021

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Macroencapsulation systems have been developed to improve islet cell transplantation but can induce a foreign body response (FBR). The development of neovascularization adjacent to the device is vital for the survival of encapsulated islets and is a limitation for long-term device success. Previously we developed additive manufactured multi-scale porosity implants, which demonstrated a 2.5-fold increase in tissue vascularity and integration surrounding the implant when compared to a non-textured implant. In parallel to this, we have developed poly(ε-caprolactone-PEG-ε-caprolactone)-b-poly(L-lactide) multiblock copolymer microspheres containing VEGF, which exhibited continued release of bioactive VEGF for 4-weeks in vitro. In the present study, we describe the next step towards clinical implementation of an islet macroencapsulation device by combining a multi-scale porosity device with VEGF releasing microspheres in a rodent model to assess prevascularization over a 4-week period. An in vivo estimation of vascular volume showed a significant increase in vascularity (* p = 0.0132) surrounding the +VEGF vs. −VEGF devices, however, histological assessment of blood vessels per area revealed no significant difference. Further histological analysis revealed significant increases in blood vessel stability and maturity (** p = 0.0040) and vessel diameter size (*** p = 0.0002) surrounding the +VEGF devices. We also demonstrate that the addition of VEGF microspheres did not cause a heightened FBR. In conclusion, we demonstrate that the combination of VEGF microspheres with our multi-scale porous macroencapsulation device, can encourage the formation of significantly larger, stable, and mature blood vessels without exacerbating the FBR.

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Section: Discussionmentioning

confidence: 99%

Assessing the Effects of VEGF Releasing Microspheres on the Angiogenic and Foreign Body Response to a 3D Printed Silicone-Based Macroencapsulation Device

et al. 2021

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“…The significant difference between the left and right sides for polygons adds complexity when planning the procedure. We have, recently, described a porous refillable reservoir and a minimally invasive procedure to deliver it between muscle layers in a pig study, with securement to the fascia via a minimally invasive scope and trocar system [ 51 ]. We have shown that a space can be created, and a reservoir (similar size as discussed here) deployed in an atraumatic manner and secured with current minimally invasive fixation tools.…”

Section: Discussionmentioning

confidence: 99%

“…We have shown that a space can be created, and a reservoir (similar size as discussed here) deployed in an atraumatic manner and secured with current minimally invasive fixation tools. These refillable reservoirs are manufactured from soft materials such as thermoplastic polyurethane, with an elastic modulus approximately 15 MPa [ 52 ], similar to the tissue extracellular matrix [ 53 ], which enables minimally invasively delivery through a trocar [ 51 ] and also allows conformation of the device during bending and twisting within the tissue plane. This favourable interaction with the surrounding environment will be essential for long-term device performance but also patient comfort.…”

Section: Discussionmentioning

confidence: 99%

Developing a morphomics framework to optimize implant site-specific design parameters for islet macroencapsulation devices

McDermott

Robinson

Holcombe

et al. 2021

J. R. Soc. Interface.

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Delivering a clinically impactful cell number is a major design challenge for cell macroencapsulation devices for Type 1 diabetes. It is important to understand the transplant site anatomy to design a device that is practical and that can achieve a sufficient cell dose. We identify the posterior rectus sheath plane as a potential implant site as it is easily accessible, can facilitate longitudinal monitoring of transplants, and can provide nutritive support for cell survival. We have investigated this space using morphomics across a representative patient cohort (642 participants) and have analysed the data in terms of gender, age and BMI. We used a shape optimization process to maximize the volume and identified that elliptical devices achieve a clinically impactful cell dose while meeting device manufacture and delivery requirements. This morphomics framework has the potential to significantly influence the design of future macroencapsulation devices to better suit the needs of patients.

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“…Hence, multiple islet infusions are often required to reverse insulin dependence. [ 186 ] Many of the commercially available [ 5,80 ] and research stage devices [ 86,176,187 ] have incorporated features (tubing and self‐sealing subcutaneous or transcutaneous ports) to enable the repeated delivery of cell cargo. This design consideration is particularly relevant to allow dosing and cargo adjustment if one thinks about future incorporation of continuous sensing of implant function.…”

Section: Minimizing Foreign Body Responsementioning

confidence: 99%

Design Considerations for Macroencapsulation Devices for Stem Cell Derived Islets for the Treatment of Type 1 Diabetes

et al. 2021

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Stem cell derived insulin producing cells or islets have shown promise in reversing Type 1 Diabetes (T1D), yet successful transplantation currently necessitates long‐term modulation with immunosuppressant drugs. An alternative approach to avoiding this immune response is to utilize an islet macroencapsulation device, where islets are incorporated into a selectively permeable membrane that can protect the transplanted cells from acute host response, whilst enabling delivery of insulin. These macroencapsulation systems have to meet a number of stringent and challenging design criteria in order to achieve the ultimate goal of reversing T1D. In this progress report, the design considerations and functional requirements of macroencapsulation systems are reviewed, specifically for stem‐cell derived islets (SC‐islets), highlighting distinct design parameters. Additionally, a perspective on the future for macroencapsulation systems is given, and how incorporating continuous sensing and closed‐loop feedback can be transformative in advancing toward an autonomous biohybrid artificial pancreas.

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Implantable Therapeutic Reservoir Systems for Diverse Clinical Applications in Large Animal Models

Cited by 15 publications

References 52 publications

Assessing the Effects of VEGF Releasing Microspheres on the Angiogenic and Foreign Body Response to a 3D Printed Silicone-Based Macroencapsulation Device

Assessing the Effects of VEGF Releasing Microspheres on the Angiogenic and Foreign Body Response to a 3D Printed Silicone-Based Macroencapsulation Device

Developing a morphomics framework to optimize implant site-specific design parameters for islet macroencapsulation devices

Design Considerations for Macroencapsulation Devices for Stem Cell Derived Islets for the Treatment of Type 1 Diabetes

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