The design of implanted biomaterials and devices should involve strategies for the prevention of inflammation and fibrosis that enhance the functional lifespan of the implants. The delivery

of drugs and the transplantation of therapeutic cells to specific organs or tissues can be enhanced by the use of implants, be them soft biomaterials or devices. However, the inherent

immunogenicity of foreign materials poses substantial hurdles to their long-term functionality and safety. Implantation triggers a cascade of foreign-body responses that can lead to

inflammation, fibrosis and even implant failure. Although some degree of immune response is inevitable, excessive or chronic inflammation can be detrimental. For example, the foreign-body

implant longevity requires strategies for the modulation of host immune responses. These can involve the selection of materials with inherent biocompatibility, loading them with

immunomodulatory agents and modifying their interfaces with host tissue to reduce protein adsorption and immune-cell adhesion. This issue of _Nature Biomedical Engineering_ highlights

innovations in the modulation of host immune responses to implanted biomaterials and devices towards improving their longevity and functionality, specifically the incorporation of

immunomodulators into biomaterial formulations, the development of biocompatible or biodegradable materials that reduce inflammation and promote the formation of blood vessels, and the

engineering of pre-vascularized implantation sites. In one Article, Chima Maduka, Christopher Contag and colleagues describe a study of immunometabolic responses to implanted biomaterials,

with the aim to improve their effectiveness. They show that the activation state and composition of immune cells surrounding polylactide — a clinically used biodegradable polymer — are

substantially affected by metabolic cues in the polymer’s microenvironment, and investigated strategies for altering it to stimulate pro-regenerative responses. Specifically, the authors

show that by incorporating metabolic inhibitors into the polymer the immune microenvironment around the implant can be metabolically altered (in particular, by lowering the involvement of

glycolytic pathways) to reduce inflammation and promote pro-regenerative responses. Kin Man Au, Andrew Wang and co-authors describe in another Article an alternative strategy to enhancing

implant functionality, in their case in the context of autoimmune disease: creating a localized immunosuppressive environment around an implant to protect it from immune attack.

Specifically, they functionalized nanofibres with immune checkpoint molecules, immunomodulatory drugs and immunosuppressive molecules to suppress the activation of T cells. In mouse models

of ulcerative colitis, subcutaneous injection of the immunosuppressive nanofibres along with colon epithelial cells and decellularized colon extracellular matrix reduced inflammation in the

animals’ colons. Rather than simply mitigating the overall immune response to the implant, the authors designed the bioengineered niche to selectively manipulate specific immune pathways

that support colon-specific immune tolerance. Complications of implant failure may also be avoided by delving into the involved cellular mechanisms. This is exemplified by the work of Xu

Yang and co-authors, who studied the cellular drivers of peri-implant fibrosis. The authors discovered that skeletal stem cells expressing the leptin receptor (Fig. 1) are crucial (yet not

solely responsible) for the generation and maintenance of fibrotic tissue surrounding medical-grade titanium implants (which are typically used as joint replacements). Specifically, the

cells contributed to the excessive production of collagen and other extracellular matrix components. The authors also show that selectively targeting and eliminating these cells (genetically

or by inhibiting the adhesion G-protein-coupled receptor F5, a key regulator of the cells’ function) in a mouse model of knee arthroplasty led to substantial reductions in peri-implant

fibrosis. Ensuring the long-term survival and function of implanted cells is particularly challenging in islet transplantation for the treatment of type 1 diabetes. In another Article, A. M.

James Shapiro, Minglin Ma and co-authors report a strategy that overcomes limitations of islet-transplantation methods with regard to the hostile subcutaneous environment (which limits

vascularization and increases the risk of fibrotic overgrowth). Specifically, the authors show that creating a pre-vascularized subcutaneous ‘pocket’ via a clinically approved nylon catheter

(implanted for 4–6 weeks) allows for the subsequent implantation of a geometrically matching thread-like device (a surgical nylon thread coated with islet-seeded alginate) for islet

encapsulation without the need for immunosuppression. In immunocompetent syngeneic, allogeneic and xenogeneic mouse models of diabetes, this strategy reversed diabetes in the animals, likely

owing to improved oxygenation of the encapsulated islets and to their physiological responsiveness to glucose. The functionality of pancreatic β-cells can be replicated by subcutaneously

injected glucose-responsive formulations of insulin, as shown in an Article by Zhen Gu, Jinqiang Wang and colleagues. They report a formulation of a complex of gluconic-acid-modified

recombinant human insulin and a polymer (poly-l-lysine modified with 4-carboxy-3-fluorophenylboronic acid) that releases insulin in response to changing glucose levels. The authors show in

mice and minipigs with type 1 diabetes that, under normoglycaemic conditions, the complex released small amounts of insulin, providing a sustained basal level of the hormone, and that at

elevated glucose concentrations the binding of glucose to the phenylboronic acid moieties disrupted the complex, promoting insulin release. Notably, the formulation led to week-long

normoglycaemia in the animals and did not cause the formation of a fibrous capsule around the subcutaneous injection site, which the authors attribute in part to the gradual biodegradability

of the polymer. A more clinically actionable strategy when treating diabetes would involve improving the efficacy of current treatments. In this regard, Zhiqiang Cao and collaborators show

how to increase the lifespan of continuous subcutaneous insulin infusion catheters, whose efficacy is limited by the need for frequent replacements. The authors developed an injectable and

biodegradable zwitterionic gel that can be injected directly into the skin before inserting the tip of the commercially available catheters for insulin infusion to increase their functional

longevity and performance in diabetic mice and minipigs. The gel led to substantially reduced pro-inflammatory markers in the tissue surrounding the catheter, which remained unoccluded for

more than 6 months in the mice and for 13 days in the minipigs (whereas untreated catheters failed after about 1.5 months in the mice and in about 2 days in the minipigs). The studies

highlighted here are notable examples of progress in the design of biomaterials that can actively modulate or evade detrimental host immune responses to improve the safety, efficacy and

longevity of transplanted cells or of implanted biomaterials or devices. Yet, the discussed strategies may face hurdles in human testing, including potential systemic immune suppression,

off-target effects and unpredictable outcomes owing to variabilities in human immune responses. It is also clear that a deeper understanding of the complex interplay between biomaterials and

the immune system at the molecular, cellular and tissue levels can guide the design of advanced biomaterials that better integrate with the body and that function effectively for longer.

RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Overcoming immune hurdles to implant longevity. _Nat. Biomed. Eng_ 8, 1191–1192 (2024).

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