Researchers can restore sensation to breast cancer survivors

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About half of Prof. Stacy Lindau’s patients over the last decade have had breast cancer and express new difficulties with sexual function during and after treatment. That’s now several hundreds of women.

“One of the common problems women complain of is the loss of sensation in their breast after mastectomy with reconstruction,” or even after just a lumpectomy, said Lindau, a leading University of Chicago professor of obstetrics and gynecology.

“In the U.S. alone, 100,000 women a year have one or both breasts removed. That’s a lot of women losing an important body part.”

Lindau set out looking for evidenced-based solutions to these problems and came up empty-handed. So she’s now leading the Bionic Breast Project, an interdisciplinary research program at UChicago applying bionic technologies to restore post-mastectomy breast function.

“It was with these observations and substantial suffering among my patients that I went looking for a solution to the problem of lost sensation and more generally, loss of function in the female breast in the context of breast cancer,” Lindau said.

In looking for answers, she came across media stories about successes with penile transplants. What struck her about this coverage was the rarity of the conditions that would warrant this transplant, in relation to the significant investment that has been made in restoring penile function.

Additionally, Lindau said she was given hope by the fact that the success of these procedures was being judged not just by the cosmetic appearance, but also by three aspects of penile function: urinary, sexual and reproductive function.

Advances in bionics emerged as a good place to look, and Lindau quickly connected with Prof. Sliman Bensmaia, a renowned neuroscientist who studies sensory information in the nervous system and the brain; he previously developed a robotic arm that allowed a paralyzed man to control the arm with his brain and feel the sensation of touch.

Bensmaia, the James and Karen Frank Family Professor of Organismal Biology and Anatomy, said the project dovetails nicely with his previous work, but the target population is much larger.

Using some of the concepts developed for the bionic hand, the researchers plan to embed a flexible sensor array under the skin of mastectomy patients. Activated any time the nipple-areolar complex is touched, the sensor array sends signals to a series of electrodes that stimulate the patient’s residual intercostal nerves – nerves that used to interface with the breast.

“You can create vivid sensations of touch by electrically activating the nerves of the hand,” explained Bensmaia, noting that the Bionic Breast will foster re-embodiment of the patient’s chest.

“It can feel like a part of their body again,” he said.

The work is backed by the National Cancer Institute R21 grant mechanism, which is intended to encourage exploratory research and gives the researchers two years to establish a working relationship and do the foundational and development work needed to warrant a longer-term, larger-scale investment.

As part of this, the researchers also are collating a list of subjective and objective criteria by which to measure breast function.

“If we want to study the relationship between breast cancer treatment and breast function, we need a measure to assess breast function – and that did not exist,” said Lindau, whose lab is leading this work with input from a patient advisory board that has been helping define the right questions to ask and the right people with which to collaborate.

While Lindau’s team is well on its way to developing a measure that can also be used by others, Bensmaia is in parallel conducting the physical testing to quantify breast sensation.

His team has developed a rig that enables the researchers to precisely quantify sensory perception in the breast – an adaptation of one used in their work studying hand sensation.

Testing the sensor technology subcutaneously for an extended period of time is the last technology development piece left to complete. Sihong Wang, an assistant professor at the UChicago Pritzker School of Molecular Engineering, is developing the tissue-like pressure sensors that can be structurally and functionally integrated into the Bionic Breast.

“Such sensors can work similarly as the sensing receptors in the breast for sensing physical contact/movement, by converting it to an electrical signal,” Wang said.

“Our major steps are to build such sensors with tissue-like soft materials that are biocompatible for implantation, and to use the electrical signal to communicate with the artificial peripheral neural devices that Sliman will build.”

Mastectomy and reconstruction often happen in multiple stages, during which the researchers can implement the sensor array, giving them the opportunity to prototype without subjecting patients to additional surgeries.

“It’s much less invasive than bionic hands, which require a special surgery to make that work,” Bensmaia said.

The researchers also plan to apply for an additional grant, which will help lay the foundation for studies in animal models and humans.

“This has the clearest path forward in just about anything I’ve ever done. All the components are in place,” Bensmaia said. “I am very confident this is going to work and help millions of women around the world.”


The Role of Breast Sensation in Female Sexual Function

Loss of breast sensation after mastectomy is a prevalent, well-established, and distressing outcome for women and their partners that – despite best practice guidelines – is rarely addressed in the course of breast cancer care (Snell et al., 2010; Marshall and Galea, 2015; Flitcroft et al., 2017).

Advances in breast preservation and reconstruction (including skin-sparing, nipple-sparing, deep inferior epigastric artery perforate, and neurotization techniques) aim to better preserve breast sensation to touch.

However, these procedures typically have strict eligibility criteria, sensation outcomes are highly unpredictable, and normal breast sensation is rarely preserved (Magarakis et al., 2013; Zhou et al., 2018).

Although surgical innovation continues to evolve (Peled and Peled, 2019), preservation of the distal branches of the intercostal nerves supplying the breast is typically infeasible for women with breast cancer due to concern about oncologic safety (Liebig et al., 2009).

Breast transplantation has not been documented. However, transplantation requires immunosuppression, an unacceptable risk for a breast cancer patient, and would likely yield a poor sensory outcome.

Although concern for sensory outcomes after mastectomy is growing, the majority of research paradigms in breast reconstruction after mastectomy have focused on aesthetic or cosmetic rather than functional outcomes.

Breast sensation is an important aspect of breast function for two reasons. First, the sense of touch is essential to embodiment or a person’s feeling that a body part belongs to her (Botvinick and Cohen, 1998).

Patients seen at the University of Chicago Program in Integrative Sexual Medicine have said about their breasts after reconstruction: “They look great in a sweater, but they are dead to me” and “Aesthetically, they look awesome, but they do nothing for me.”

These statements corroborate zoologist Stephen Wainwright’s maxim, especially apt for sense of touch: “Structure without function is a corpse” (Wainwright, 1988). The disconnect between body appearance and function can have deleterious consequences on overall physical, psychic, and social function.

Second, breasts play an important role in female sexual function (Levin and Meston, 2006). From a patient with numb breasts after reconstruction: “When you don’t feel something and you know someone is touching them, it’s a turn-off.”

Some women describe aversion to and avoidance of sex or even a feeling of anger, disgust, or dissociation during sexual contact with their numb breasts after mastectomy. Nipple–areolar complex sensation is an essential component of arousal and orgasm physiology for many people and their partners (Levin, 2006).

Sexual dysfunction affects as many as three quarters of women with breast cancer and is at least partially attributable to loss of breast sensation (Ganz et al., 1999; Fobair et al., 2006; American Psychiatric Association, 2013; Raggio et al., 2014; Rojas et al., 2017).

Preservation and Restoration of Sexual Function in Men With Cancer

In contrast to breast cancer care, medical decision-making for men with prostate cancer is routinely informed by evidence about sexual function outcomes associated with treatment options (American Urology Association, 2007).

Preservation and restoration of sexual function in men with prostate cancer has been identified as an important patient-centered outcome. The effort to improve sexual function outcomes for men after prostate cancer (American Urology Association, 2007; Grondhuis Palacios et al., 2017; Elliott and Matthew, 2018; Girodet et al., 2019) has driven substantial surgical innovation over the last two decades, supported in part by the U.S. National Institutes of Health, and has produced significant improvements (Willis et al., 2012).

In 2016, a man with penile cancer (a cancer type affecting < 0.001% of men) underwent a successful penile transplant. Cosmesis was not the only outcome of interest—the measure of success in this and a subsequent case also required restoration of urinary, reproductive, and sexual function (Grady, 2016; Merwe et al., 2017).

Between 2014 and 2018 at least four successful penile transplants have been accomplished worldwide. These breakthrough efforts to preserve male sexual function, including in the context of penile cancer, both inspire and legitimize innovation to preserve breast function for the large and growing population of women with or at elevated risk of breast cancer (Grady, 2016; Merwe et al., 2017; McDaniels, 2018).

Toward a Bionic Breast

One approach to restore function to reconstructed breasts is to apply bionic technologies that have been successful in sensitizing prosthetic hands. Sensitization of the prosthetic hand is achieved by electrical stimulation of residual nerves delivered through chronically implanted arrays of electrodes, which evokes sensations that are referred to the phantom hand (Saal and Bensmaia, 2015).

The referred sensations are highly localized and repeatable, and their magnitude can be manipulated by modulating the amplitude or frequency of microstimulation (Graczyk et al., 2016). These phenomena can be exploited by connecting pressure sensors on the bionic hand to electrodes with somatotopically appropriate projection fields.

For example, the pressure sensor on the index fingertip of the bionic hand drives stimulation though an electrode that evokes sensations on the index fingertip. Bionic hands endowed with artificial tactile feedback confer greater dexterity to users than do insensate ones (Ortiz-Catalan et al., 2014; Valle et al., 2018; George et al., 2019).

Furthermore, the incorporation of artificial touch leads to a greater embodiment of the hand (Marasco et al., 2011; Schiefer et al., 2016; Page et al., 2018; Rognini et al., 2018; Valle et al., 2018) and restores some of the key psychosocial components of manual touch, including the ability to experience pleasure from touching a loved one (Graczyk et al., 2018, 2019; Cuberovic et al., 2019; George et al., 2019).

This strategy can be straightforwardly applied to reconstructed breast. An array of sensors would be implanted under the skin of the breast centered on the nipple (Figure 1), an application for which recent advances in flexible sensory technology can be leveraged (Boutry et al., 2019; Niu et al., 2019; Ruth et al., 2019).

The output of the sensors would drive electrical stimulation through arrays implanted in residual intercostal nerves III–VI, which carry sensory signals from the breast. Various technologies have been developed to provide electrical interfaces with the peripheral nerves, any one of which would be appropriate for this application (Saal and Bensmaia, 2015).

The sensory encoding algorithms—which convert patterns of sensor output into trains of electrical stimulation—would be implemented in a hermetically sealed electronic circuit that would be lodged in the implant or just under the skin.

Such an implantable circuit—with the appropriate inputs and outputs—has already been developed for bionic hands (Peterson et al., 2016). The spatial extent of the sensor array under the reconstructed breast will depend on which intercostal nerves are implanted with stimulating arrays.

Minimally, the array will span the nipple–areolar complex, but may cover the entire breast if all four intercostal nerves are accessed. Given the current state of technology, the principal bottleneck in the spatial resolution of artificial touch is set by the electrical interface with the nerve, not the sensors, so sensor pitch will not be a major design specification for the sensor sheets.

The current consensus is that the tactile sensibility of the breast is similar to that of the hand, so sensory encoding models developed for the hand (Saal et al., 2017; Okorokova et al., 2018) can likely be applied to the breast, accounting for differences in the relative densities of the different subtypes of tactile nerve fibers.

A limitation of this approach is that thermal sensation – key to affective and sexual touch – cannot be restored through electrical stimulation because thermoreceptive nerve fibers are small and unmylienated and thus insusceptible to electrical stimulation.

Similarly, nerve fibers implicated in affective touch – c-tactile fibers – will not be activated by the electrical interface. With these caveats, restoration of tactile sensation alone is liable to have a major impact on the sexual and psychosocial function of the breast, based on its documented impact on manual function.

The U.S. National Cancer Institute has invested in the Bionic Breast Project, a new, interdisciplinary program of research that is laying the foundation of basic knowledge – including development of subjective and objective measures of female breast function – to apply bionic technologies to restoration of breast function after mastectomy.

In addition to improving outcomes for women with breast cancer, this work could hold promise for improved outcomes after reconstruction for traumatic breast injury and for people undergoing elective breast surgery, for example, for gender affirmation.

Figure 1. Schematic illustration of the Bionic Breast concept for a breast reconstructed using an implant. An array of pressure sensors (A) is placed under the reconstructed or tattooed nipple and the surrounding region. The output of the sensors triggered by pressure applied to the skin is converted into electrical stimulation pulse trains via a hermetically sealed electronic circuit (B), shown here to be encased in the breast implant. The electrical stimulation pulse trains are delivered through one or more electrode arrays (C) implanted around or in the residual intercostal nerve(s) that innervated the nipple areolar complex before mastectomy. Nerve stimulation results in a sensation projected to the nipple areolar region. Much of this technology has already been developed to restore sensation to bionic hands.

More information: Stacy T. Lindau et al. Using Bionics to Restore Sensation to Reconstructed Breasts, Frontiers in Neurorobotics (2020). DOI: 10.3389/fnbot.2020.00024

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