This is a single-center, double-blind, randomized, placebo-controlled, sequential Phase II trial of human recombinant hyaluronidase injections in individuals with post-stroke upper limb muscle stiffness. The investigators will recruit 56 subjects, who will be randomized to receive either the intervention or normal saline injections (first injection), and then the intervention the participants did not receive first (second injection). All individuals will receive the treatment by the end of the study.

1. To test the effect of hyaluronidase injections on upper limb outcomes. The investigators will test the hypothesis that compared to placebo, human recombinant hyaluronidase injections will increase passive range of motion (ROM) in the most affected joint of the upper limb (primary outcome), isometric muscle strength or force generation capacity using Maximum Voluntary Contraction (MVC) on electromyography (EMG), reduce upper limb motor impairment as measured by the Fugl-Meyer (FM) scale, and improve function as measured by the Wolf Motor Function Test (WMFT).
2. To evaluate the effect of hyaluronidase on neural and non-neural components of muscle stiffness. The investigators will test the hypothesis that compared to placebo, intramuscular (IM) hyaluronidase will modulate the passive and potentially also the active component of the stretch reflex, reduce stiffness and improve arm motor control.
3. To determine the effect of hyaluronidase on intramuscular glycosaminoglycans (GAG) content. The investigators will test the hypothesis that compared to placebo, IM hyaluronidase will reduce the T1rho relaxation times in the biceps and triceps muscles of the affected arm.

Inclusion Criteria:

• Ischemic or hemorrhagic stroke 4-180 months prior
• Moderately-severe muscle stiffness
• Lack of full passive and active range of motion in at least 2/4 areas (shoulder, elbow, forearm, wrist) in the hemiparetic upper limb;
• Willingness to have MRI, complete all clinical assessments, and comply with study protocols;
• Ability to give informed consent and HIPPA certifications; and

Exclusion Criteria:

• treatment of spasticity with Botulinum toxin or intrathecal baclofen within the past six months, phenol injections within the past 12 months, or ongoing adjustment of anti-spastic medications;
• other neurologic condition that may affect motor response (e.g., Parkinson's disease, amyotrophic lateral sclerosis (ALS), MS);
• clinically significant cognitive dysfunction with score <19 on Folstein's Mini Mental Status Examination or depression with score >10 on the Patient Health Questionnaire-9 (PHQ-9);
• pregnancy;
• known hypersensitivity to hyaluronidase;
• claustrophobia;
• standard contraindications for MRI
• Any condition that will preclude the patient from completing the protocol as determined by the PI