Somatotopic Configuration of Distal Residual Limb Tissues in Lower Extremity Amputations

Historical Background

Lower extremity amputation is among the oldest known surgical procedures in medical history.
Despite the passage of over two millennia, however, relatively little has changed in the
operative approach. Currently, lower limb amputation is indicated most frequently for lower
extremity compromise due to severe peripheral vascular disease, followed in short order by
trauma, tumors, infections and congenital limb deficiencies. Estimates of frequency of lower
limb amputations range from 30,000-40,000 cases per year in the United States alone.

Normal function of the lower limb is enabled through the interplay of multiple muscle groups
acting in concert. Ambulation 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 lower extremity
exist in a balanced agonist/antagonist milieu in which volitional activation of one muscle
leads not only to its contracture, but also passive stretch of its opposite. Changes in
muscle tension manifest through these changes lead to stimulation of specialized receptors
within the muscle fibers 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.

However, the standard operative approach to lower limb amputation at either the below knee
(BKA) or above knee (AKA) level obliterates many of the dynamic relationships characteristic
of the uninjured lower extremity. Initial exposure is accomplished through either a
stair-step (BKA) or fishmouth (AKA) 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 infrastructure in order to achieve definitive closure. The
rudimentary approximation of tissues in the distal limb in these approaches 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 results in impaired ambulatory function with prosthetics, but
also manifests as pathological sensory perception of the extremity in the form of phantom
limb and phantom pain symptomatology.

To date, providers and patients have tolerated the limitations of these approaches due to the
fairly simplistic goal of lower limb amputation: to provide a stable, padded surface for
prosthesis mounting. Historically, lower limb prostheses have afforded amputees the
opportunity to recover at least some measure of ambulatory function. Standard lower limb
prostheses currently afford the wearer the walk in a rudimentary fashion, as well as
occasionally run. However, such devices have generally not been able to recapitulate the
complex biomechanics of the human lower limb due to limited ranges of motion and lack of
feedback control. These limitations have resulted in substantially altered kinematics in
lower limb amputees that are associated with derangements in energy expenditure profiles that
worsen with laterality and ascending level.

An age is dawning, however, in which the capabilities of modern prostheses are broadening
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 markedly enhanced degrees of freedom over prior
models. Such prostheses have been demonstrated to markedly improve the energy expenditure of
amputees who utilize them appropriately. Even more advanced prostheses are currently under
development that incorporate the ability to provide active intrinsic limb control to
facilitate complex motor actions such as dancing and balancing on one leg. In addition,
prototype prosthetics are currently being developed that have the potential to offer sensory
feedback - both tactile and positional - in a manner never before witnessed. Such
prosthetics, while not yet available commercially, are presently being utilized in
experimental settings.

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

Previous Pre-Clinical or Clinical Studies

Recognition of the increased need for effective neural interfaces for prosthetic limbs has
been evidenced by an 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
direct and indirect 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 progressive
foreign body reactions leading to impulse degradation over time.

As the limitations of brain interfaces have become more evident, focus has shifted to 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 significant neurological crosstalk and interference in
biological models.

As such, the most promising efforts regarding peripheral nerve interface development are now
within the realm of biological systems. The two leading models in this sphere are as follows:

- Targeted Muscle Reinnervation (TMR): TMR is a technique whereby a series of nerve
transfers is utilized to reinnervate specific target muscles to create additional
prosthetic control sites after proximal limb amputation. These nerve transfers offer
intuitive control of distal prostheses because the reinnervated muscles are controlled
by the same nerves that once innervated the amputated limb. Signals created by the
residual nerves are amplified by the recipient muscles, which are captured by surface
electrodes and transduced to the distal prosthesis. TMR procedures have been performed
on more than 40 patients to date. Limitations of this technique, however, include the
finite number of available electromyographic signal sites due to anatomic constraints
and issues with long-term signal fidelity.

- Regenerative Peripheral Nerve Interfaces (RPNI): 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. Unlike TMR, the RPNI muscle is not recruited from an otherwise normally
innervated proximal muscle; instead, it is constructed as a free graft from
orthotopically sourced donor tissue. The muscle segment is gradually reinnervated by the
redirected nerve ending, which then promotes volitional activation of the muscle segment
when triggered by the central nervous system. As in TMR, intuitive control occurs
because the reinnervated muscles are controlled by the same nerves that once innervated
the amputated limb. Unlike TMR, however, there are no limitations on anatomic sites and
there does not appear to be problems with long-term signal fidelity.

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
have already experienced limb loss.

Rationale and Potential Benefits

This clinical protocol proposes an iteration of the RPNI model, with the intent of
incorporating these surgical constructs into the design of lower limb amputations at the time
of limb sacrifice. Given the success of this technique to date, the investigators believe
that incorporation of innervated muscle segments into residual limb design has the potential
to provide lower limb amputees with a biological interface for unprecedented prosthetic motor
control that is not only high resolution but also highly intuitive and capable of restoring
limb proprioception. In addition, it is anticipated that allowing amputees to have greater
control of advanced prostheses may offer the potential to normalize gait kinematics, thereby
correcting alterations in energy expenditure that have been previously reported. Such
measures hold the promise of optimizing the functional and overall health of lower limb
amputees, thereby reducing the morbidity currently associated with the amputee status.

Specific Aims

The hypothesis of this research protocol is that we will be able to redesign the manner in
which lower limb amputations are performed so as to include biological actuators that will
enable the successful employment of next generation lower extremity prostheses. The specific
aims of the project are as follows:

1. To define a standardized approach to the performance of a novel operative procedure for
both below knee (BKA) and above knee (AKA) amputations

2. To measure the degree of volitional motor activation and excursion achievable in the
residual limb constructs, and to determine the optimal configuration and design of such
constructs

3. To describe the extent of proprioceptive and other sensory feedback achievable through
the employment of these modified surgical techniques

4. To validate the functional and somatosensory superiority of the proposed amputation
technique over standard approaches to BKA and AKA

5. To develop a modified acute postoperative rehabilitation strategy suited to this new
surgical approach

Inclusion Criteria:

- Males or females between the ages of 18 and 65

- Candidates for elective unilateral or bilateral lower extremity amputation at either
the above knee or below knee 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 #1801183130 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 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.