A Visionary Approach to OA: Help the Body Heal Itself 

By Linda Rath | Aug. 10, 2023

American medicine may not be known for disruptive innovations and risky gambles, but the ambitious Advanced Research Projects Agency for Health (ARPA-H), approved in 2022, aims to change that. An independent funding agency within the historically cautious National Institutes of Health, ARPA-H’s mandate is to invest in bold, revolutionary technologies with the potential to transform health and health outcomes quickly and equitably.

ARPA-H is modeled on the Defense Advanced Research Projects Agency (DARPA), a research and development arm of the U.S. Department of Defense. DARPA was crucial in developing the internet, global positioning systems (GPS), drones and Siri. ARPA-H intends to be bold, risk-taking and nimble to aid researchers and patient advocates who believe high-risk, high-reward projects can lead to transformative change.

ARPA-H is one of several Advanced Research Projects Agencies, focused on different industries, such as energy and infrastructure. They are staffed by term-limited program managers with vision, expertise and autonomy to fund and run a research project using a milestone-based contract approach. ARPA-H managers typically serve for three years – six at most – a timeframe that reflects the agency’s sense of urgency and aversion to staleness and complacency.

Ross Uhrich, a biomedical engineer, former Navy lieutenant commander and oral and maxillofacial surgeon, is one of ARPA-H’s first program managers. As someone who treats patients at Walter Reed National Military Medical Center, he has a personal and professional interest in creating revolutionary treatments for osteoarthritis (OA), a disease in desperate need of them. 

No Cure, Few Treatments

OA causes pain and disability for more than 240 million people worldwide, including 32 million or so in the U.S. It has no cure and few medical treatments other than joint injections and pills for pain, which are only moderately effective and can have serious side effects. Weight loss and exercise may offer better pain relief and can slow OA but not stop it. No current therapy ultimately prevents the disease from getting worse. Many people with extensive damage or discomfort eventually opt for surgery to replace the arthritic joint with an artificial implant made of metal alloys and plastic or ceramic parts. Implants may not eliminate all pain and they have risks and complications, including a lengthy recovery and, in some cases, the need for additional surgeries. And OA research has been difficult partly because OA takes years to develop, which makes trials prohibitively expensive.

ARPA-H’s first program addresses the great challenge of osteoarthritis. The program, known as Novel Innovations for Tissue Regeneration in Osteoarthritis (NITRO), is intended to upend the current model by focusing on regenerative therapies to heal and replace cartilage and bone affected by OA.

Reimagining What’s Possible

Regenerative medicine is a relatively new and potentially transformative alternative to traditional health care for conditions that have no cure and few treatments. Instead of focusing on disease management, which aims to minimize symptoms and improve quality of life, regenerative medicine harnesses breakthroughs in biomedical engineering, biomaterials and cell therapies to support the body’s innate ability to repair and heal itself. It has been critical in improving cardiovascular disease and shows promise for OA and other conditions, including diabetes, cancer and neurodegenerative disorders.

Uhrich considers OA the starting point.

“OA is a very admirable and large goal to tackle, but the therapeutics we are looking to create though NITRO are hopefully a platform paradigm shift as well as an OA paradigm shift. Our initial goal is OA, but if we succeed, we have the opportunity to revolutionize the care of a whole lot of other diseases and disease processes. Our goal is not to just fix OA and call it a day.”

Regenerative therapies caught fire in the early 2000s when athletes began using platelet rich plasma (PRP) in an effort to heal their battered hamstrings and rotator cuffs. Since then, doctors have used PRP to treat everything from knee pain to tendon tears and hair loss. Researchers have also developed methods for patching articular cartilage – the slippery covering on the ends of bones – using a patient’s own (autologous) cells. Surgical procedures, like matrix-induced autologous chondrocyte implantation (MACI), can repair small areas of cartilage damaged by injury or age. They can’t treat a disease as diffuse as OA but may help prevent or postpone it. Research into new treatments, like in vivo tissue engineering (creating tissue inside the patient’s body), gene editing and gene therapy are moving forward but not fast enough for many OA patients.

Regenerating Bone and Cartilage 

The NITRO program focuses on three well-defined technical areas: bone regeneration, cartilage regeneration and replacement joints made entirely of human cells. In the first two, the goal is to create treatments that stimulate the body to fully repair damaged tissue. Most are nonsurgical although regenerative bone therapies may include an arthroscopic (minimally invasive surgery) approach. Cartilage repair will have two formulations – a systemic approach for multiple joints as well as local injections, patches, gels, biomaterial sheets and a litany of other therapies for people with less damage. Depending on their need, patients might receive cartilage therapy, bone therapy or both.

In a sense, these therapies are a more complex and fully realized version of PRP, which itself doesn’t repair tissue damage, but instead activates the body’s natural healing response. If successful, these therapeutics would stimulate the natural healing mechanisms within the joint. 

“We don’t want people coming into the doctor’s office to stave off degeneration; we want them to come for regeneration,” Uhrich says.

Unlike PRP, cartilage and bone regeneratives would ideally be needed only once, although Uhrich says that may not always be possible.

“It has to be plausible given the current state of science. That’s the reason we say, ‘ideally it’s one and done.’ The maximum [need for treatment] would be once a year.”

Building a New Joint From Scratch

The third area of focus involves building a replacement joint from human cells. One type of joint would use donor (allogeneic) cells and one would use a patient’s own tissue. For people with traumatic injuries needing immediate reconstruction, a patient-specific allogeneic joint could conceivably be built in 24 hours. Those who can wait 30 days – the time it takes to grow the tissue – could have a joint made from their own cells. Critically, both types of replacements would not be anchored with plates and screws but would integrate fully with the surrounding tissue and never fail.

“A lot of people are doing a lot of different things in terms of total joint reconstruction. But to do a whole implant with cartilage and bone and a vascular network, I haven’t seen anything like that in the industry. It won’t necessarily be easy, but it might be easier than putting a massive load-bearing plate in the joint,” Uhrich says.

He expects most people with a human cell implant to return to full function in four to six weeks instead of three months to a year – the current timeframe. 

“The goal is to return everyone to the quality of life they expect, without an asterisk,” he says. “If we’re not massively beating the current standard of care, then we’re not making the waves we need to be making in this health care agency for effective change.”

How NITRO Works: BAAs and Timeline

Like other government agencies, both ARPA-H and NITRO use a Broad Agency Announcement (BAA) to solicit proposals for research and development. Unlike a grant, which provides a specific statement of purpose, a BAA presents a problem in need of a solution. Since there is no predetermined method for solving the problem, it’s expected that BAAs will spark innovation that may help solve big challenges. Compared to typical grant-based research, which usually has a narrow focus, a BAA contract is, as the name suggests, broad. This means it is higher risk but also potentially higher reward. The robust funding reflects this.

Broad doesn’t mean free-range, however. The NITRO program has strictly defined milestones and deliverables, with an aggressive timeline: five years from proposal acceptance to a scalable, affordable, marketable solution that can pass muster with the FDA.

NITRO proposals were due July 28, 2023. They will be vetted by an internal science review board and experts who will decide which are the most promising. There is no predetermined number of selected proposals; Uhrich says they will be self-limiting. 

“We could have one super team that tackles everything or 10 individual groups. Performers (the ARPA-H term for award winners) are selected based not on metrics but on the scientific and technical merits of their proposals.” 

Once in, performers will be monitored “on an extremely granular level” all along the way. “If they aren’t meeting our metrics, they won’t continue in the program,” Uhrich says. “It’s not like a grant-based system where you say, ‘Here’s a bunch of money, and we’ll see you at the end.’ The justification there is that we don’t have time to waste on bad science. Everything we do will be validated and verified.”

Equity Is Baked In

OA disproportionately affects women and people of color. Indigenous peoples and Alaska Natives have a higher incidence than any other groups in the U.S., and rates of OA are increasing among Black Americans and Hispanic women. One of the many things that sets NITRO apart from traditional research is its commitment to equity in clinical trials and beyond. 

Women will represent more than half of participants in the NITRO clinical trials, and other races and ethnicities will be proportionately represented. Each performer team will be required to have an equity officer to ensure equity. 

Uhrich says they will also be bringing on another equity officer to serve as the industry expert who will advise him, his team and performers. And they will have listening sessions for the most affected patients.

“I want to know how they interface with their doctors, do they take the bus there, how do they pay, what’s their coverage – these things will play into how we advise our performers. If they are making very beautiful but very expensive therapeutics, then we have failed, frankly.”

Uhrich says there are ways to cut costs, including streamlining research and development and the FDA regulatory process. They are also with working Medicare and Medicaid to figure out a payment pipeline for these therapies. But ultimately, the question of who pays to treat the under-insured and uninsured – many of whom may need OA therapies the most – hasn’t been answered. 

“We are exploring every possible avenue to make sure we don’t miss the most critical patients,” Uhrich says.

Uhrich is confident NITRO will be successful. “This is a totally different model that has worked time and time again through DARPA. I think we have a very multi-faceted agency where we can make these things happen,” he says.