Diagnosis marks the beginning of any successful therapy. Because many medical conditions progress asymptomatically over extended periods of time, their timely diagnosis remains difficult, and this adversely affects patient prognosis. Focusing on hypercalcemia associated with cancer, we aimed to develop a synthetic biology-inspired biomedical tattoo using engineered cells that would (i) monitor long-term blood calcium concentration, (ii) detect onset of mild hypercalcemia, and (iii) respond via subcutaneous accumulation of the black pigment melanin to form a visible tattoo. For this purpose, we designed cells containing an ectopically expressed calcium-sensing receptor rewired to a synthetic signaling cascade that activates expression of transgenic tyrosinase, which produces melanin in response to persistently increased blood Ca²⁺. We confirmed that the melanin-generated color change produced by this biomedical tattoo could be detected with the naked eye and optically quantified. The system was validated in wild-type mice bearing subcutaneously implanted encapsulated engineered cells. All animals inoculated with hypercalcemic breast and colon adenocarcinoma cells developed tattoos, whereas no tattoos were seen in animals inoculated with normocalcemic tumor cells. All tumor-bearing animals remained asymptomatic throughout the 38-day experimental period. Although hypercalcemia is also associated with other pathologies, our findings demonstrate that it is possible to detect hypercalcemia associated with cancer in murine models using this cell-based diagnostic strategy.

诊断标志着任何成功疗法的开始。由于许多医疗状况会在较长时间内无症状地进展，因此难以及时诊断，这会对患者的预后产生不利影响。着眼于与癌症相关的高钙血症，我们旨在使用工程化细胞开发一种合成生物学启发的生物医学纹身，该工程细胞将（i）监测长期血钙浓度，（ii）检测轻度高钙血症的发作，并且（iii）通过皮下反应黑色素黑色素的堆积形成可见的纹身。为此，我们设计了含有异位表达的钙敏感受体的细胞，该细胞重新连接至合成的信号传导级联反应，该信号传导激活转基因酪氨酸酶的表达，该酪氨酸酶响应持续增加的血液钙而产生黑色素。²⁺。我们证实，这种生物医学纹身产生的黑色素产生的颜色变化可以用肉眼检测到并进行光学定量。该系统在带有皮下植入的封装工程细胞的野生型小鼠中得到验证。接种了高钙血症性乳腺癌和结肠腺癌细胞的所有动物均出现纹身，而接种了正常血钙性肿瘤细胞的动物中未见纹身。在整个38天的实验期内，所有荷瘤动物均无症状。尽管高钙血症也与其他病理相关，但我们的发现表明，使用这种基于细胞的诊断策略，可以在鼠模型中检测与癌症相关的高钙血症。