A Novel Approach to Upper Extremity Amputation to Augment Volitional Control and Restore Proprioception

Upper extremity amputation is among the oldest known surgical procedures in medical history,
with many of its technical principles having first been elucidated by Hippocrates. Despite
the passage of more than two millennia, relatively little has changed in the operative
approach to upper limb sacrifice. An estimated 58,000 patients in the United States currently
suffer from upper extremity limb loss at either the above elbow (AEA) or below elbow (BEA)
level, and the prevalence of upper limb amputation is expected to rise to approximately
95,000 patients by 2050.

Normal function of the upper limb is enabled through the dynamic interplay of multiple muscle
groups acting in concert. Manual dexterity is a remarkably orchestrated biomechanical process
that is dependent upon a complex feedback loop involving the central and peripheral nervous
systems and the musculoskeletal system. In their native state, the muscles of the upper
extremity exist in a balanced agonist/antagonist situation in which volitional activation of
one muscle leads not only to its contracture, but also to passive stretch of its opposite.
Changes in muscle tension manifest through this interaction of agonist and antagonist units
lead to stimulation of specialized receptors within the muscle fibers (e.g., muscle spindle
fibers and Golgi tendon organs) that transmit joint position information to the cerebral
cortex. Such feedback, in conjunction with cutaneous sensory information from skin
mechanoreceptors, provides us with a sense of limb proprioception that ultimately enables
high fidelity limb control, even in the absence of visual feedback.

Unfortunately, the standard operative approach to upper limb amputation at either the AEA or
BEA level obliterates many of the dynamic relationships characteristic of the uninjured upper
extremity. Initial surgical exposure is typically accomplished through a fishmouth-pattern
incision, followed by progressive transection of muscles, vessels, nerves and bone at the
level of the incision. Tissues distal to the site of structural transection are discarded,
regardless of whether or not there may be viable segments, and the proximal residual muscles
are layered over the distal transected bone in order to provide insulation to this exposed
osseous surface. The surrounding skin is then advanced over the bone/muscle construct in
order to achieve definitive closure. The rudimentary approximation of discordant tissues in
the distal limb in this approach results in a disorganized scar mass in which normal dynamic
muscle relationships are destroyed. The uncoupling of native agonist/antagonist muscle
pairings results in isometric contraction of residual muscle groups upon volitional
activation, producing incomplete, unbalanced neural feedback to the brain that results in
aberrant perception of residual limb position. Such disturbed feedback not only leads to
impaired limb function with prostheses, but also manifests as pathological sensory perception
of the extremity in the form of phantom limb and phantom pain symptoms.

To date, the limitations of these approaches have been tolerated due to the fairly simplistic
goal of upper limb amputation: to provide a stable, padded surface for mounting a prosthesis.
Historically, upper limb prostheses have afforded amputees the opportunity to recover at
least some measure of upper limb function. However, such devices have generally not been able
to recapitulate the complex biomechanics of the human upper limb due to limited ranges of
motion and lack of feedback control. These limitations have resulted in reported upper limb
prosthesis rejection rates ranging from 23% to 45%, including both body-powered and
myoelectric devices.

However, the capabilities of modern prostheses are now expanding remarkably. Technological
advances including increasingly miniaturized electronics, wireless communications and
ever-refined positional sensors have enabled prosthetic developers to create next-generation
bionic limbs with greatly enhanced degrees of freedom over prior models. Even more advanced
prostheses are currently being developed that have the potential to offer sensory feedback -
both tactile and positional - in a manner never before seen. Such prosthetic devices, while
not yet available commercially, are presently being studied in experimental settings. For
example, the Defense Advanced Research Projects Agency (DARPA) recently issued a request for
proposals under the Hand, Proprioception and Touch Interfaces (HAPTIX) Program incorporating
an upper limb prosthesis including six degrees of freedom at the wrist, thumb and all digits,
10 pressure sensors capable of providing sensory feedback, and joint angle and velocity
sensors capable of providing joint position data.

Despite these technological advances in prosthesis development, surgical methods regarding
management of the residual limb have not kept pace with these enhanced prosthesis
capabilities. Classic techniques of upper limb amputation do not provide innervated
interfaces that can serve as relays for complex prosthetic control; without such biological
actuators in the residual limb to provide afferent and efferent conduits for information
exchange, next generation prostheses are of little use. Stated another way, next generation
prosthetic devices currently incorporate drivers and sensors capable of providing far more
enhanced functionality than ever before seen, but standard approaches to limb amputation do
not deliver a way to effectively link these prosthetics to their intended beneficiaries. An
evolution in the manner in which upper limb amputations are performed - one that will provide
a biological interface that will allow upper limb amputees to take advantage of the enhanced
capabilities offered by the remarkable prostheses currently under development - is now
required.

Recognition of the increased need for effective neural interfaces for prosthetic limbs can be
seen in the expanding number of efforts in this sphere over the past decade. Initial efforts
to provide high-resolution control of distal prostheses were focused primarily on indirect
and direct brain interfaces, either through placement of electroencephalographic scalp
sensors or implantable parenchymal electrodes, respectively. However, such endeavors have
been plagued by poor resolution, inconsistencies in signal acquisition and, in the case of
implantable devices, progressive foreign body reactions leading to impulse degradation over
time.

As the limitations of brain interfaces have become more evident, focus has shifted instead to
peripheral control loci. Efforts in this vein have included direct peripheral nerve
interfaces including interposed sieves and cuffs designed to transduce electrical signals
directly from individual nerve fascicles to distal prostheses. Such monitors have, however,
shown little clinical promise due to progressive nerve compression secondary to scarring, as
well as to significant neurological crosstalk and interference in biological models.

The most promising efforts regarding peripheral nerve interface development are now within
the realm of biological systems. These models consist of configurations in which native
tissues are innervated with distal nerve endings to create biological actuators for distal
prosthesis control and feedback. The two leading models in this sphere are as follows:

- Targeted Muscle Re-innervation (TMR): Pioneered by Dumanian and Kuiken et al, TMR is a
technique whereby a series of nerve transfers is used to re-innervate specific target
muscles to create additional prosthesis control sites after distal limb amputation.

- Regenerative Peripheral Nerve Interfaces (RPNI): Championed by Cederna et al, RPNI
offers an alternative version of an innervated biological interface. An RPNI is a
surgical construct that consists of a non-vascularized segment of muscle that is coapted
to a distal motor or sensory nerve ending.

While both TMR and RPNIs have demonstrated promise in offering improved functionality to
patients who have already undergone amputation, neither technique has been incorporated into
a fundamental redesign of the way in which amputations are performed in the first place; in
all cases of clinical implementation of TMR or RPNIs reported to date in the literature,
these techniques have been employed to further optimize the functionality of patients who had
already experienced limb loss.

The clinical protocol proposes a reinvention of the manner in which upper limb amputations
are performed, building upon several of the principles established in the work already
performed in the realm of TMR and RPNIs. As elaborated below, the core innovation is the
utilization of distal limb tissues that would ordinarily be sacrificed in the course of
standard lower limb amputations to provide the substrate for natively innervated pairings of
agonist/antagonist muscles capable not only of intuitive, volitional motor activation but
also proprioceptive feedback. Conceptually, this idea consists of physical linkage of
biologically opposed muscles (e.g., the biceps and triceps) such that when neurologically
triggered contraction of one muscle is effected, simultaneous stretch of its partner is also
achieved, resulting in observable motion of the dyad and stimulation of standard
proprioceptive pathways. The investigators have named this construct the agonist-antagonist
myoneural interface (AMI).

The manner in which this dynamic agonist/antagonist muscle concept may be operationalized
clinically depends upon whether or not intact, innervated and vascularized native muscles are
present at the time of operative intervention. Over the past five years, the research group
has developed experimental models for a variety of clinical scenarios through a series of
preclinical investigations in both murine and caprine populations.

If healthy native muscle is available as a reconstructive substrate, coaptation of the distal
ends of disinserted agonist/antagonist pairs may be incorporated into the design of the
residual limb; when coupled with a native synovial canal as a gliding interface, a
pulley-like system can be established to provide a dynamic muscle construct. Construction of
AMIs in a rat model have demonstrated preservation of construct muscle bulk, viability over
time and production of graded afferent signals in response to ramp and hold stretches in a
manner similar to native muscle architecture. Furthermore, performance of an amputation at
the transtibial level with incorporation of AMI construction in a goat model has demonstrated
clear coupled motion of the agonist-antagonist pair in the presence of both natural neural
commands and artificial muscle stimulation.

Based on these proof of concept animal studies, the investigators hypothesize that the AMI
offers the potential to provide a biological relay for volitional control that is superior to
other neural interface strategies, with the additional benefit of being able to restore limb
proprioception. When coupled with an appropriately adapted next-generation prosthesis, the
AMI thus may provide the first biological mechanism to achieve true closed-loop neural
interactivity with a mechanical limb.

The investigators here propose a three-year, prospective, controlled assessment of the
functional and somatosensory advantages of the modified amputation model in an upper
extremity scenario. The investigators believe this model has the potential to provide upper
limb amputees with a biological interface that offers not only unprecedented, high-resolution
motor control of prostheses, but also is highly intuitive and capable of restoring limb
proprioception. If manifest, these augmented capabilities may result in improved
functionality and overall health outcomes, including more robust return to work status and
diminished psychological strain.

Inclusion Criteria:

- Males or females between the ages of 18 and 65

- Candidates for elective unilateral or bilateral upper extremity amputation at either
the above elbow or below elbow level due to traumatic injury, congenital limb
deformities or progressive arthritis

- Must demonstrate sufficiently sound health to undergo the operative procedure,
including adequate cardiopulmonary stability to undergo general anesthesia
(specifically, American Society of Anesthesiology Class I or II)

- Must have intact inherent wound healing capacity

- Must demonstrate adequate communication skills to convey the status of their
sensorimotor recovery throughout the postoperative phase,

- Must exhibit proper level of motivation to comply with postoperative follow up
requirements

- Must be willing to also consent to protocol #1901643758 at Massachusetts Institute of
Technology (approved by the Committee on the Use of Humans as Experimental Subjects)
as some outcome measures will be assessed under this affiliated study

Exclusion Criteria:

- Patients beyond the stated age restrictions

- Those with severe illness rendering them unable to undergo the operative procedure
safely (e.g., unresolved sepsis or cardiopulmonary instability manifest as documented
coronary artery disease and/or chronic obstructive pulmonary disease)

- Patients with active infections, particularly deep infections in the arm to be
amputated

- Patients who are taking immunosuppressive agents

- Patients with impairment in inherent wound healing pathways, such as those with
primary connective tissue disorders or those on chronic steroid therapy

- Patients with extensive peripheral neuropathies (diabetic or otherwise) that would
potentially inhibit appropriate reinnervation of the surgical constructs

- Active smokers; those patients willing to undergo tobacco cessation will need to be
completely abstinent from tobacco use for at least 6 weeks preoperatively

- Patients who are unable to provide informed consent and those with a demonstrated
history of poor compliance

- Pregnant women will not be considered due to the potential risks of general anesthesia

Patients will not be excluded from participation in the study on the grounds of minority
status, religious status, race or gender. Non-English speaking patients will not be
excluded from the study; interpreters will be made available to them for translation of
both verbal interactions and written documents.