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ViviGen® Cellular Bone Matrix

Value Analysis Brief

ViviGen® Value Analysis Brief | 21

Executive Summary

Challenges with Current Bone Graft Materials

ViviGen Solution

Patient-Centered Care

• Morbidity10,11 and complications such as infection,

hematoma/seroma, fracture, nerve and vascular injuries,

chronic donor site pain, hernias, scarring, and poor

cosmetic outcome11,12 have been associated with Iliac

crest bone graft (ICBG), and the variability of graft

quality resulted in the need for alternative

osteobiologic materials, such as recombinant human

bone morphogenetic protein-2 (rhBMP-2).

• Reports of serious and potentially life-threatening

complications, such as neurologic deficits, osteolysis,

and heterotopic ossification, began emerging soon

after the approval of rhBMP-2.13,14

• Complications associated with ICBG and rhBMP-2 can

be avoided with use of ViviGen because it represents

a composite allograft that can be considered a viable

alternative to autograft.1

• ViviGen bone cells in vitro do not elicit an immune

response.15

• Every donor for ViviGen must meet LifeNet Health’s strict

medical and behavioral risks assessment in addition to

microbial and serological testing.16

• The availability of an alternative to an autograft or

rhBMP-2 could increase the patient population eligible

for bone grafting interventions.

Economic Value

• Healthcare costs, duration of surgery, and length of

stay are concerns for physicians, hospitals, and payers.

– Post-operative costs (inpatient and outpatient care)

of up to $39,967 for rhBMP-2 and $42,286 for ICBG

have been reported in the literature. 20

• Complications from ICBG used with or without

rhBMP-2 are costly to treat. Mean costs of treating a

post-operative complications ranged from $10,888 to

$46,852 if a revision procedure was necessary based

on published data. 20

• Use of ViviGen represents a viable alternative to

autograft1, and thereby, eliminates the possibility of

costly complications associated with the use of ICBG

and rhBMP-2.

Challenges with Current Bone Graft Materials

ViviGen Solution

Clinical Effectiveness

• Successful bone grafting requires 3 properties:

1. Osteogenesis (osteoprogenitor cells)

2. Osteoinduction (bone morphogenic proteins

(BMPs) and other growth factors)

3. Osteoconduction (scaffold)

• In vitro studies show that ViviGen contains all the

properties required for bone formation and can be

used as an alternative to an autograft.

• ViviGen contains lineage-committed bone cells1 –

it is the first cellular allograft focused on bone cells.7

• ViviGen cells have been shown to exponentially

proliferate post-thawing.1

Operating Room Efficiency

• Estimating the amount of bone graft prior to the

surgical procedure, may lead to a delay in operating

room time if additional graft material is needed and

the duration of surgical time is increased to

accommodate thawing time.

• The packaging for ViviGen enables a rapid thaw time

of 5 minutes or less – crucial for cell viability and

optimizing OR time.9

• The 5-minute or less thaw time of ViviGen (vs. 30

minutes for most competitors) optimizes product

availability as needed in the operating room and

promotes OR efficiency.

CLINICAL VALUECLINICAL VALUE

3 ViviGen® Value Analysis Brief | 4

BACKGROUND

The use of bone graft technology is routinely employed within Orthopedic trauma surgery to promote a biological

response that will assist the timely healing of musculoskeletal injuries. An ideal bone graft substitute possesses

osteoconductive, osteoinductive, and osteogenic properties to facilitate bone healing.22

EpidemiologyThe need for bone graft is rising in orthopedic reconstructive surgery with the increasing number of arthroplasties,

fusions, and limb salvage procedures. It has been estimated that more than 500,000 allograft bone grafts are

being recovered annually in the United States alone.23 Fresh autogenous cancellous and, to a lesser degree, cortical

bone are benchmark graft materials that allograft and bone substitutes attempt to match in in vivo performance.23

The availability of autograft is, however, limited, and recovery is often associated with donor-site morbidity and

increased healthcare costs.23 Hence, there is a substantial need for autograft alternatives for orthopedic

applications.

Clinical BurdenFracture nonunions of long bones represent a significant clinical challenge and socioeconomic burden, associated

with high complication rates and the potential for poor long-term outcomes.24 Nonunions are defined as fractures

that fail to heal.25 Despite advances in surgical technique, fracture fixation, and adjuncts to healing, femoral

nonunion continues to be a significant clinical problem.26,27 Fractures may fail to unite because of the severity of

the injury, damage to the surrounding tissues, inadequate initial fixation, and demographic characteristics of the

patient.26,27

A retrospective study of a U.S. managed care medical claims database showed that, from a retrospective cohort

of 853 patients with tibial shaft fractures, 99 (12%) had a nonunion diagnosis associated with their tibia fracture

treatment.28 Greater than 70,000 hospitalizations, 800,000 office visits, and 500,000 hospital days have been

attributed to tibial shaft fractures in the U.S. annually.29

One epidemiology study in Rochester MN in 1987 demonstrated that the incidence of ankle fractures is

approximately 187 fractures per 100,000 people each year.30 This rate is increasing in many industrialized

countries, most likely due to growth in the number of people involved in athletics and in the size of the elderly

population.30,31 The incidence of more complex foot and ankle fracture patterns is also increasing, and failure to

achieve anatomic fracture reduction results in poor functional outcomes. Open injury, diabetes, and peripheral

vascular disease are strong risk factors predicting a complicated short-term postoperative course.32

Economic BurdenNonunions in tibial shaft fractures are associated with substantial healthcare resource use, common use of

NSAIDs or opioids, and high per-patient costs.28 All categories of care (except emergency room costs) were

more expensive in nonunion patients than in those that achieved bony union: median total care cost $25,556

vs. $11,686 (p<0.001).28

The estimated economic burden of foot and ankle surgery in the Medicare population was estimated to be

$11 billion in 2011, up 38.2% since 2000.33 Considerable healthcare costs and productivity losses are

associated with foot and ankle surgery, and trends in chronic disease indicate that the cost of foot and ankle

fractures is likely to increase.33


UNMET NEED

Challenges with Existing Interventions for Bone Grafting

Iliac Crest Bone Graft (ICBG)

The most common source of cortical and cancellous bone has been the iliac crest, frequently called iliac crest bone

graft (ICBG).12 This is due to the availability of adequate quantity of bone graft with progenitor cells, growth

factors, and structural support.34,35 However, the recovery of ICBG requires an additional surgical step during the

index procedure which often results in complications and discomfort for the patient.10,11,12 The incidence of

morbidity and complications associated with recovering bone from the iliac crest has been reported to range

between 6% and 30%.11 Potential complications include infection, hematoma/seroma, fracture, nerve and

vascular injuries, chronic donor site pain, hernias, scars, and poor cosmetic outcome.10,11,12 The complications and

morbidity may persist regardless of the recovery site or technique, or even the surgeon’s skills;11,12 and they often

come with a substantial cost, especially when hospitalization is prolonged or complications occur that require

further management.18,36

Bone Morphogenic Protein (BMP)

Despite the excellent spinal fusion rates promoted by recombinant human bone morphogenic protein (rhBMP)-2,

the increasingly reported adverse outcomes associated with rhBMP-2 usage have created real concerns.14 rhBMP-2

was approved in 2002 by the U.S. Food and Drug Administration (FDA) as a bone graft substitute for a single-

level anterior lumbar interbody fusion, and in 2004 for treating acute, open tibial shaft fractures that have been

stabilized with IM nail fixation after appropriate wound management. However, rhBMP-2 has been used in other

ways that have not been reviewed or cleared by the FDA.13 Several years following FDA approval, a series of

publications surfaced that detailed the serious adverse events associated with rhBMP-2 including heterotopic

ossification, osteolysis, seroma/hematoma, infection, allergic reaction, scar formation, arachnoiditis, dysphagia

and life threatening retropharyngeal swelling (anterior cervical surgery), increased incidence of neurologic deficits

(radiculopathy, myelopathy), retrograde ejaculation, and cancer.13,14

Traditional Allografts

Traditional allografts have osteoconductive and osteoinductive properties, however they lack viable osteogenic

cells. These allografts depend on native stem cells/precursors and osteoblasts from the recipient to populate the

allograft and can be influenced by the recipient’s health conditions.

Mesenchymal Stem Cells (MSCs)

Processing methods have been developed to attempt to retain viable bone precursors such as mesenchymal stem

cells (MSCs) within the donor’s original bone niche to stimulate bone formation.38 MSCs are the progenitors of

osteoblasts, which drive the synthesis and mineralization of the bone matrix. The number of MSCs and their

physiological function have been shown to progressively decline with age38 and disease state37 of an individual

and, therefore, poses a challenge for effective clinical application of these cells to repair bone defects in

individuals receiving traditional allograft bone products. Moreover, since MSCs are capable of differentiation into

multiple cell types, it is difficult to precisely control the differentiation of MSCs into a specific cell type. In addition

to differentiating into bone cells, MSCs are also capable of differentiating into other mesenchymal cell types

including fibroblasts, chondrocytes, and adipocytes dependent on the growth factors provided (Figure 1).

FIGURE 1: Proliferation of mesenchymal stem cells (MSCs).

MARROw TENDON/ LIGAMENT

Marrow StromaTendogenesis/

Ligamentogenesis

CARTILAGE MUSCLEBoNE

osteogenesis Chondrogenesis Myogenesis

MSC Proliferation

Mesenchymal Stem Cell (MSC)


OPPORTUNITIES FOR IMPROVED CLINICAL EFFECTIVENESS wITH VIVIGEN

BENEfITS of LINEAGE-CoMMITTEd BoNE CELLSSince they are human derived, lineage-committed bone cells, (i.e. osteoblasts and osteocytes), offer a better

potential for bone repair than MSCs by:

• depositing high quality, differentiated bone;2,3

• promoting vascularization of the scaffold;4

• secreting chemotactic factors to recruit host osteoblasts;5 and

• stimulating osteogenesis in already resident MSCs.6

ViviGen contains lineage-committed bone cells1 – it is the first cellular allograft focused on bone cells.7

Lineage-committed bone cells are better for bone repair than mesenchymal stem cells (MSCs).2,3,4,5,6

The osteogenic property of a graft is imparted by living cells capable of producing new bone. Mesenchymal

stem cells (MSCs) can differentiate into several types of cell lineages including bone, cartilage, muscle, marrow,

and tendons or ligaments. ViviGen represents a paradigm shift in the field of bone and tissue repair because it

is the first cellular allograft to be focused on recovering, processing, and protecting viable lineage-committed

bone cells (Figure 2).1,7

The processing of bone for ViviGen involves depleting the bone of bone marrow and MSC's from the bone

retaining essential, viable bone cells including osteoblasts, osteocytes, and bone lining cells (Figure 3).

FIGURE 3: ViviGen contains lineage-committed bone cells,

including bone lining cells, osteoblasts, and osteocytes.

FIGURE 2: Proliferation of mesenchymal stem cells (MSCs).

Bone lining cells Osteoclasts Osteoblasts

Osteocytes

Maturation

Differentiation

Lineage Progression

Commitment

Proliferation

MSC Proliferation

Mesenchymal Stem Cell (MSC)

CARTILAGE MUSCLE MARROw TENDON/ LIGAMENT

osteogenesis Chondrogenesis Myogenesis Marrow StromaTendogenesis/

Ligamentogenesis

BoNE


Pre-clinical studies suggest bone cells remain at the defect site longer,2 directly participate in the

bone formation process,2,3 and deposit a higher quality of bone than MSCs.2,3,4

• Tortelli et al. (2010)2 seeded ceramic scaffolds with green fluorescent protein (GFP)-labeled murine MSCs or

GFP-labeled murine osteoblasts and implanted them into immunocompromised mice. MSCs directed the

formation of bone of host origin by activating the endochondral ossification process, whereas osteoblasts directly

participated in the formation of new bone through an intramembranous ossification process.2 Only osteoblast-

seeded implants contained bone-depositing cells of donor origin. MSC-seeded implants showed no cells of donor

origin after 30 days and led to the development of a tissue-engineered bone of host origin (Figure 4).2

FIGURE 4: osteoblasts out-performed MSCs in both bone quantity and bone quality.

3 days 30 days 60 days

MSC

oB

• Reichert et al. (2011)3 seeded TCP scaffolds with ovine-marrow derived MSCs or osteoblasts and implanted

them into a severe combined immunodeficiency mouse. Ectopic bone formation (i.e, bone volume,

maturation, and density) was found to be much more robust in the scaffold seeded with osteoblast compared

to MSCs.3 The scaffolds seeded with osteoblasts also had higher mineralization than those seeded with MSCs

and BMP-7 combined.

• The ability of bone cells to promote vascularization was demonstrated in a study of primary human osteoblasts

pre-seeded on silk fibroin micronets by Ghanaati et al. (2011).4 Osteoblasts were shown to migrate throughout

the entire scaffold and produce extensive bone matrix in vitro (Figure 5).4 Osteoblasts induced a more rapid and

significantly higher level of vascularization of the scaffold, with microvessels homogenously distributed

throughout the scaffold, than silk fibroin alone with no pre-cultivation (Figure 5).4 The findings showed that

osteoblasts can produce not only bone matrix but also soluble factors which can serve to instruct host

endothelial cells to migrate, proliferate, and initiate the process of scaffold vascularization, which is critical to

bone healing (Figure 5).4

FIGURE 5: Human osteoblasts promote vascularization.

Osteoblast recruitment to the site of future bone formation is essential for skeletal development, bone

remodeling, and fracture healing.5,6

• Nakasaki et al. (2008)5 showed that IGF-I secreted from osteoblasts induced directed cell migration of osteoblasts,

promoted cell spreading, and regulated cell polarization in a monolayer model of wound healing.

– These results suggest a major role for IGF-I in osteoblast migration and contributed to the general

understanding of osteoblast recruitment during bone formation and repair.5

• Birmingham et al. (2012)6 investigated the role of biochemical signaling from osteocytes and osteoblasts

to understand how these cells direct osteogenic differentiation of MSCs.

– The in vitro intracellular phosphatase assay suggested that osteocytes are more influential than osteoblasts

in stimulating osteogenesis in MSCs.6

– Moreover, it was found that osteoblasts and osteocytes work in concert to secrete biochemical signals

and synergistically stimulate the osteogenic differentiation of MSCs.6

OSTEOBLASTS PROMOTE HIGH QUALITy BONE FORMATION AND VASCULARIzATION

** Difference between groups is statistically significant (p<0.05)

Note: In vitro performance is not necessarily indicative of clinical performance in human subjects.

3

2

1

0

vess

els/

mm

2

**

**

Sf+HoB 14d Sf+HoB 24h Control

B

3

2

1

0

vess

els/

mm

2

**

**

Sf+HoB 14d Sf+HoB 24h Control

A


The ViviGen lineage-committed bone cells are already committed and ready to produce calcium deposition.

when stimulated with a standard osteogenic differentiation media, a substantial deposition of calcium was

seen in the ViviGen derived cells as early as day 7. when allowed to differentiate to 14 - 21 days, extensive

matrix deposits were evident by their positive red staining for calcium in the entire well¹ (Figure 6).

FIGURE 6: ViviGen lineage-committed bone cells are already committed

and ready to produce calcium deposition, days 7, 14, and 21.

7 days 14 days

donor A

7 days 21 days

donor B

ViviGen contains all the properties required for bone formation and can be used

as an alternative to an autograft.1

ViviGen Cellular Bone Matrix comprises the 3 essential components required for bone formation:1

1. Corticocancellous chips provide the natural scaffold for bone formation

2. Demineralized bone provides osteoinductive properties due to naturally-occurring BMPs

3. Live lineage-committed bone cells capable of directly facilitating bone synthesis

DONOR RECOVERy AND PROCESSING TIME DIRECTLy AFFECTS CELL VIABILITy

• LifeNet Health developed a Xeno-free cryo solution to optimize cell viability.15

• Cells can be left in thawed cryopreservant for up to two hours and maintain 96% cell viability.15

The cells within ViviGen are maintained in a viable state during processing and cryopreservation.9

RECoVERy ANd PRoCESSING METHodS PRoTECT BoNE CELL

Viability• ViviGen is only recovered from the hemi-pelvis and femoral heads based on clinical publications citing those

areas contain the highest population of cells.15

• At every step of the processing of ViviGen, LifeNet Health has focused on maintaining the highest level of

bone cell viability by decreasing the time required for recovery and processing (see figure 7).7

• ViviGen is recovered, processed and placed into cryopreservation within 72 hours.

• Cell atrophy begins at the time of donor death and continues at an increasing rate as time passes. By achieving

the cryopreservation 24 hours sooner than competitive MSC-based cellular allografts, more cells are preserved.7,15

FIGURE 7: Timing of ViviGen cryopreservation.

RecoveRy

≤ 24 HRS

PRocessing

≤ 48 HRS

cRyoPReseRvation

≤ 72 HRS


IMPROVED PROCEDURAL EFFICIENCy

The packaging for ViviGen enables a thaw time of 5 minutes or less –

rapid thawing is crucial for cell viability.9

PACkAGING of VIVIGEN oPTIMIzES CELL VIABILITyThe basic principle for successful cryopreservation while maintaining cell viability

is a controlled slow freeze and a rapid thaw.8 The packaging design of ViviGen

(see Figure 8) is unique:

• The thin walls of the ViviGen packaging allow for efficient energy transfer, which

facilitates a slow freeze and rapid thaw.9

• The rapid heat transfer of the ViviGen packaging not only allows pouches of all sizes

to thaw in 5 minutes, but is also essential for cell viability.9

• The rapid thaw prevents ice crystals from forming intracellularly during thawing,9

ultimately maintaining viability.8

• The port at the end of the ViviGen pouch allows for the quick and efficient removal of

the cryopreservation media and rinsing solutions.9

ViviGen cells have been shown to exponentially proliferate post-thawing.1

THAwEd VIVIGEN CELLS HAVE A RoBUST PRoLIfERATIoN PRofILE In vitro studies have demonstrated the growth potential of cryopreserved ViviGen bone matrix from multiple

donors using a highly sensitive cell viability assay.1 Bone particles cryopreserved in ViviGen packaging were thawed

and rinsed according to the Instructions for Use (IFU).1 Three replicates of 1 mL of bone particles from each donor

were placed in individual wells in a 24 well plate for viability studies.1 The bone cells within ViviGen demonstrated

a robust proliferation profile over time, showing a sigmoidal growth pattern (Figure 9).1

FIGURE 9: Exponential proliferation of bone cells was observed with ViviGen from

2 different donors post-thawing1

FIGURE 8: ViviGen cryopreserved

in custom-manufactured

packaging.

• The viable bone tissue is cryopreserved in a specialized packaging system to preserve cell viability as well as

growth potential and bone formation upon thawing.1,9

• Consistent results demonstrating cell viability and proliferation were seen for ViviGen bone matrix from

multiple donors.1,9

• Due to the proprietary processing methods, ViviGen maintains a population of viable bone cells capable of

exponential growth.1,9

300

250

200

150

100

50

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Ala

mar

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0 5 10 15 20 25

donor A – Bone Chips

Days of Culture

300

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donor B – Bone Chips

Days of Culture


PATIENT-CENTERED CARE

INCREASEd PATIENT PoPULATIoN foR BoNE GRAfTING INTERVENTIoNS Use of rhBMP-2 is contraindicated in certain patient populations (refer to IFU for full details). Recovery of

autologous bone is undesirable in certain patient populations. The availability of an alternative to an autograft

or rhBMP-2 could increase the patient population eligible for bone grafting interventions.

Complications of Autologous Bone Grafting Interventions Avoided• The morbidity associated with ICBG recovery, the limited supply for fusions, and the variability of graft quality

resulted in the development of alternative osteobiologic materials such as rhBMP-2.13

• Chronic ICBG recovery site pain and discomfort is reported by a significant percentage of patients undergoing

this procedure more than three years following surgery, and these complications are associated with worse

patient-reported disability.10

– At a mean of greater than 3 years following surgery, a large percentage of patients continued to report

being troubled by numbness (24%), and chronic harvest site pain resulted in difficulty with household chores

(19%), recreational activity (18%), walking (16%), sexual activity (16%), their job (10%), and irritation from

clothing (9%) (Figure 11).10

FIGURE 11: Patient-reported effects of ICBG recovery that persisted more than 3 years10

0% 5% 10% 15% 20% 25% 30%

24%

19%

18%

16%

16%

10%

9%

Numbness

Difficulty with Household Chores

Difficulty with Recreational Activity

Difficulty with walking

Difficulty with Sexual Activity

Difficulty with Job

Irritation from Clothing

ViviGen is an alternative when autograft (ICBG) or rhBMP-2 are undesirable for use.

Complications associated with ICBG or rhBMP-2 can be avoided with use of ViviGen.1

The rapid thaw time of ViviGen helps ensure clinical efficiency. The 5-minute or less thaw time

optimizes product availability as needed and avoids waste associated with waiting for thawing,

and waste with excess allograft.

USE of VIVIGEN REdUCES THE NEEd To dISCARd UNUSEd doNoR MATERIAL

The rapid heat transfer of the ViviGen packaging allows pouches of all sizes to thaw in 5 minutes.9

• The rapid thawing of ViviGen enables surgeons to prepare ViviGen in situ as needed rather than trying to

estimate the amount of allograft needed ahead of surgery, which may lead to under- or over-estimation,

and ultimately waste.

– over-estimation: product in excess wastes money, time, and space.

– Under-estimation: inadequate product leads to wasted time for more thawing or potentially reduced

effectiveness of the grafting.

• The port at the end of the ViviGen pouch allows for the quick and efficient removal of the cryopreservation

media and rinsing solutions.9

FIGURE 10: Thawing time with ViviGen.7

THAwING TIME

| | | | | | | | | | |

|

| ≤ 5 minutes


Note: In vitro performance is not necessarily indicative of clinical performance in human subjects.

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Lym

phoc

yte

Prol

ifera

tion

(Brd

U In

corp

orat

ion)

Lymph 9 Lymph 12 Lymph 11 PBMC only

Lymphocytes Mixed with PBMC

Bone Cell 9 Bone Cell 12 Bone Cell 11 Post Cryo

Bone Cell 11 Pre Cryo

Bone Cells Mixed with PBMC

*(p<0.05) PBMC + Lymph > PBMC

*(p<0.05) PBMC + Bone Cell < PBMC

ABSENCE of IMMUNE RESPoNSE wITH VIVIGEN BoNE CELLS in vitro15

• An in vitro analysis demonstrated that the processing with ViviGen reduces the number of potentially

immunogenic cells from the bone marrow, also reducing the risk of eliciting an immune response (Figure 12).15

– Staining for CD45, a protein present on all hematopoietic cells and distributed throughout the immune

system, confirmed the presence of hematopoietic cells in the bone matrix prior to processing.15

– Post processing, cryopreservation and thawing, marrow components and CD45 positive cells were absent,

which confirmed that the marrow components were negligible.15

FIGURE 12: Immunohistochemistry staining of Cd45 positive cells (brown color)

preprocessing and post cryopreservation and thawing.15

• Bone cells derived from ViviGen in vitro were shown to be non-immunogenic using a mixed lymphocyte reaction

(MLR) assay (Figure 13).15 Lymphocytes from ViviGen donors were combined with peripheral blood mononuclear

cells (PBMCs) to elicit an immune reaction (lymphocyte proliferation) as the positive control.15 ViviGen-derived

bone cells from the same donors were mixed with PBMC, but rather than showing an immune reaction like the

lymphocytes, they reacted similarly to PBMC alone (no proliferation of cells), which was the negative control.15

FIGURE 13: Non-immunogenicity of ViviGen bone cells was demonstrated with mixed

lymphocyte reaction (MLR) assay.15

ViviGen bone cells, in vitro, do not elicit an immune response.15

Marrow components present pre-processing

Cd 45 (wBC) Cd 45 (wBC)

Marrow components removed post-processing, cryopreservation and thawing

• Reports of serious and potentially life-threatening complications associated with rhBMP-2 began emerging after

its approval in 2002.13,14

• An independent published review of reported data on the safety and effectiveness of rhBMP-2 versus ICBG

by the yale University Open Data Access (yODA) Project determined the following:

– The risks of any adverse event were high (77%-93% at 2 years) and similar for both groups.40

– At or shortly following surgery, pain was more common in the rhBMP-2 group (odds ratio, 1.78 [CI,

1.06–2.95]).39

– Heterotopic bone formation, dysphagia, and osteolysis may be more common with rhBMP-2.39

– In anterior cervical spinal fusion, rhBMP-2 was associated with increased risk of wound complications

and dysphagia.40

– At 24 months, cancer risk was increased with rhBMP-2 (RR, 3.45 [95% CI, 1.98–6.00], however,

the event rates were low and the increased risk was no longer apparent at 4 years.40


STRICT TESTING of VIVIGEN doNoRS

Every donor for ViviGen must meet LifeNet Health’s strict medical and behavioral risks assessment in addition

to microbial and serological testing (Figure 14).16

• LifeNet Health is a leading, federally designated Organ Procurement Organization. LifeNet Health only accepts

donors from federally designated Organ Procurement Organizations and qualified tissue recovery partners.16

• These partners are regularly audited to document that their recovery process meets current FDA regulations,

AATB standards and LifeNet Health’s own stringent guidelines.16

FIGURE 14: ViviGen donor suitability and release criteria.16

Donors must meet strict medical and behavioral risks assessment in addition

to microbial and serological testing.16

1. Initial Screening

POTENTIAL DONORS Our goal is to identify all potential medically-suitable donors. As a federally

designated Organ Procurement Organization, LifeNet Health is made aware of

every potential donor within the geography we represent. Our Call Center and

Recovery Staff are available 24 hours/7 days a week. A Medical Director is

always accessible to offer technical and/or medical assistance.

AGE All tissue is evaluated to meet appropriate age limits. ViviGen donors must

adhere to specific age limits.

PAST MEDICAL HISTORy AND CURRENT ILLNESSES

LifeNet Health reviews the potential ViviGen donor’s past medical history for

specific rule outs including cancer, diabetes, renal disease, CJD, auto-immune

diseases as well as numerous other diseases and illnesses. LifeNet Health utilizes

a medical conditions database of over 1,500 diseases and medical conditions

that affect donor suitability.

REPORT BEHAVIORAL AND SOCIAL RISK FACTORS

LifeNet Health will review the medical history reports along with an Incidence-

window Period Model to identify donors who are at risk of having a recent

infection that may not be detected by routine serology or NAT testing. The model

evaluates possible high risk behaviors based on drug use, tattoos, body art, body

modifications, and sexual behaviors. This is to minimize the risk of a donor having

a false negative screening test result for hepatitis B, hepatitis C, and/or HIV.41

POTENTIAL MEDICALLy-SUITABLE DONORS

Once the initial screening is complete, the potential ViviGen donor is recovered

and a stringent medical screening is performed.

3. Medical Screening/Processing

POTENTIAL MEDICALLy-SUITABLE DONORS

After the initial screening process, the potential medically- suitable ViviGen donor

goes through a more in-depth medical screening. Due to the sensitive nature of

ViviGen, the donor is processed in tandem with the in-depth medical screening.

CULTURE AND SEROLOGy POSITIVE RESULTS

Blood cultures and independent tissue cultures are collected. Tests for HIV and

Hepatitis are administered. Biopsy results and the initial chart are reviewed.

QUALITy CONTROL QUALITy ASSURANCE

LifeNet Health performs the following quality control testing on each lot of

ViviGen. The finished product must pass USP<71> Sterility Tests. Each lot is

tested to contain >16,000 viable bone cells per cubic centimeter (cc) post thaw.

Finally, calcium content in the demineralized bone is measured to ensure

average residual calcium levels in the optimal range of 1% to 4%. Quality

assurance compiles and places all relevant technical and medical chart

information for final review by the Medical Director.

MEDICAL DIRECTOR REVIEw The final disposition of tissue is the responsibility of the Medical Director who

makes their determination based on all relevant information including autopsy

results, medical chart, recovery and quality records. The Medical Directors Advisory

Group, a cross-departmental team unique to LifeNet Health, meets quarterly to

discuss and provide decisions regarding any technical, medical, or social issue

relevant to donor suitability. It is responsible for reviewing and modifying donor

suitability criteria and establishing new donor suitability criteria as needed.

MEDICALLy-SUITABLE DONOR The ViviGen donor is acceptable for release.

2. Recovery

Recovery technicians do positive identification and review

all medical documents. A physical inspection of the

deceased donor is administered to make sure physical

evidence matches medical information provided prior to

recovery. LifeNet Health has trained its recovery personnel

as well as LifeNet Health Partners’ recovery personnel to

take pictures and obtain biopsies of any suspicious lesions.

In 2004, the first known national recovery biopsy program

was initiated by LifeNet Health and included all of our tissue

recovery partners. Its purpose is to identify any possible

occult infection or cancer in the donor. Biopsies taken at

recovery are processed by an independent pathology lab.

Evidence of any unexpected cancer or infection will prevent

the tissue from being released.42

Not only does LifeNet Health hold the longest continuous

accreditation from the American Association of Tissue

Banks, but we have a comprehensive range of measures in

place to ensure the safety of ViviGen, including stringent

donor screening methods and release criteria. To obtain

suitable donors, LifeNet Health maintains an extensive

network of recovery partners. Additionally, LifeNet Health

is a leading, Federally designated Organ Procurement

Organization (OPO) that coordinates recovery and

transplants of organs in Virginia and part of west Virginia.


ECONOMIC VALUE

REdUCEd CoST of CoMPLICATIoNS of oTHER BoNE GRAfTING INTERVENTIoNSThe healthcare cost, duration of surgery, and length of hospital stay of ICBG and rhBMP-2 are important concerns

for physicians, hospitals, and payers. ICBG recovery and ICBG and rhBMP-2 complications have been shown to be

associated significant costs.17,18,19,20

• Data from a randomized controlled trial examining inpatient and outpatient costs for up to 2 years post-

operatively showed significant costs for both ICBG and rhBMP-2 (Figure 15).20

FIGURE 15: Healthcare costs of ICBG (n=52) and rhBMP-2 (n=50) over 2 years.

2-year total cost of IBCG $42,286

2-year total cost of rhBMP-2 $39,967

Cost of a major complication $10,888

Cost of a revision surgery for non-union $46,852

• In the ICBG group (n=52), 8 patients had complications; 20 had additional interventions, 5 of whom required

revision for nonunion. In the rhBMP-2/ACS group, 6 patients had complications, 10 had additional interventions,

and 1 required revision for nonunion.20

• VivGen may elminate the need for ICBG and BMP-2, which may result in a reduction in costly complications

and revisions.

Costs of complications associated with ICBG or rhBMP-2 may be avoided with use of ViviGen.

ViviGen is the first cellular allograft focused on lineage-committed bone cells and contains all the

properties required for bone formation.1 The morbidity and complications associated with ICBG

and rhBMP-2 may be avoided with use of ViviGen because it represents a composite allograft that

can be considered a viable alternative to autograft.1

FEATURES BENEFITS

osteogenic Contains viable lineage committed bone cells that are able to proliferate

in vitro post cryopreservation and thaw

osteoconductive Contains corticocancellous chips that provide a natural scaffold for cell

attachment, cell migration and cell proliferation.

osteoinductive Demineralization of the cortical bone exposes the natural growth factors

within the matrix

Safety Every lot is aseptically processed and all final product is tested for sterility

using USP <71> standards

Packaging The rapid heat transfer not only allows for all sizes to thaw in less than

5 minutes but is also vital for cell viability

Processing Time ViviGen reaches cryopreservation within 72 hours maximizing cell viability

24 hours sooner than competitive products

Maximized Cell Viability The processing of ViviGen is focused on protecting viable lineage

committed bone cells from recovery to implantation¹

*Please refer to the package insert for a complete list of indications, contraindications, precautions and warnings. For further information on DePuy Synthes products, please contact your local DePuy Synthes representative.

FEATURES AND BENEFITS


1. Chen SS. Osteogenic Potential of the ViviGenTM Cellular Component.

Results from In Vitro Studies. LifeNet Health® Institute of Regenerative

Medicine white Paper.

2. Tortelli F, Tasso R, Loiacono F, Cancedda R. The development of

tissue-engineered bone of different origin through endochondral and

intramembranous ossification following the implantation of

mesenchymal stem cells and osteoblasts in a murine model.

Biomaterials. 2010;31(2):242-9.

3. Reichert JC, Quent VM, Nöth U, Hutmacher Dw. Ovine cortical

osteoblasts outperform bone marrow cells in an ectopic bone assay. J

Tissue Eng Regen Med. 2011;5(10):831-44.

4. Ghanaati S, Unger RE, webber MJ, Barbeck M, Orth C, Kirkpatrick JA,

Booms P, Motta A, Migliaresi C, Sader RA, Kirkpatrick CJ. Scaffold

vascularization in vivo driven by primary human osteoblasts in concert

with host inflammatory cells. Biomaterials. 2011;32(32):8150-60.

5. Nakasaki M, yoshioka K, Miyamoto y, Sasaki T, yoshikawa H, Itoh K.

IGF-I secreted by osteoblasts acts as a potent chemotactic factor for

osteoblasts. Bone. 2008;43(5):869-79.

6. Birmingham E, Niebur GL, McHugh PE, Shaw G, Barry FP, McNamara

LM. Osteogenic differentiation of mesenchymal stem cells is regulated

by osteocyte and osteoblast cells in a simplified bone niche. Eur Cell

Mater. 2012;23:13-27.

7. Data on File at LifeNet Health.

8. Rall wF, Reid DS, Polge C. Analysis of slow-warming injury of mouse

embryos by cryomicroscopical and physiochemical methods.

Cryobiology. 1984;21(1):106-21.

9. Chen SS. Advantage of ViviGen™ Packaging. Results from In Vitro

Studies. LifeNet Health® Institute of Regenerative Medicine white

Paper.

10. Schwartz CE, Martha JF, Kowalski P, wang DA, Bode R, Li L, Kim DH.

Prospective evaluation of chronic pain associated with posterior

autologous iliac crest bone graft harvest and its effect on postoperative

outcome. Health Qual Life Outcomes. 2009;7:49.

11. Herscovici D Jr, Scaduto JM. Use of the reamer-irrigator-aspirator

technique to obtain autograft for ankle and hindfoot arthrodesis. J

Bone Joint Surg Br 2012;94(1):75-9.

12. Dimitriou R, Mataliotakis GI, Angoules AG, Kanakaris NK, Giannoudis

PV. Complications following autologous bone graft harvesting from the

iliac crest and using the RIA: a systematic review. Injury 2011;42 Suppl

2:S3-15.

13. Skovrlj B, Marquez-Lara A, Guzman Jz, Qureshi SA. A review of the

current published spinal literature regarding bone morphogenetic

protein-2: an insight into potential bias. Curr Rev Musculoskelet Med.

2014;7(3):182-8.w

14. Tannoury CA, An HS. Complications with the use of bone

morphogenetic protein 2 (BMP-2) in spine surgery. Spine J.

2014;14(3):552-9

15. Data on File. LifeNet Health® DHF 12-008

16. ViviGen™ Donor Suitability & Release Criteria. LifeNet Health®

17. Glassman SD, Carreon Ly, Campbell MJ, Johnson JR, Puno RM,

Djurasovic M, Dimar JR. The perioperative cost of Infuse bone graft in

posterolateral lumbar spine fusion. Spine J. 2008;8(3):443-8.

18. Lohmann H, Grass G, Rangger C, Mathiak G. Economic impact of

cancellous bone grafting in trauma surgery. Arch Orthop Trauma Surg

2007;127(5):345–8.

19. St John TA, Vaccaro AR, Sah AP, Schaefer M, Berta SC, Albert T, et al.

Physical and monetary costs associated with autogenous bone graft

harvesting. Am J Orthop 2003;32(1):18–23.

20. Carreon Ly, Glassman SD, Djurasovic M, Campbell MJ, Puno RM,

Johnson JR, Dimar JR 2nd. RhBMP-2 versus iliac crest bone graft for

lumbar spine fusion in patients over 60 years of age: a cost-utility study.

Spine (Phila Pa 1976). 2009;34(3):238-43.

21. De Long wG Jr, Einhorn TA, Koval K, McKee M, Smith w, Sanders R,

watson T. Bone grafts and bone graft substitutes in orthopaedic

trauma surgery. A critical analysis. J Bone Joint Surg Am.

2007;89(3):649-58.

22. Roberts TT, Rosenbaum AJ. Bone grafts, bone substitutes and

orthobiologics: the bridge between basic science and clinical

advancements in fracture healing. Organogenesis. 2012;8(4):114-24.

23. Greenwald AS, Boden SD, Goldberg VM, Khan y, Laurencin CT, Rosier

RN, American Academy of Orthopaedic Surgeons. The committee on

biological implants. Bone-graft substitutes: facts, fictions, and

applications. J Bone Joint Surg Am 2001;83(Suppl. 2, Part 2):98–103.

24. Flierl MA, Smith wR, Mauffrey C, Irgit K, williams AE, Ross E, Peacher

G, Hak DJ, Stahel PF. Outcomes and complication rates of different

bone grafting modalities in long bone fracture nonunions: a

retrospective cohort study in 182 patients. J Orthop Surg Res.

2013;8:33.

25. American Academy of Orthopaedic Surgeons, Nonunions. 2014.

26. Lynch JR, Taitsman LA, Barei DP, Nork SE. Femoral nonunion: risk factors

and treatment options. J Am Acad Orthop Surg. 2008 Feb;16(2):88-97.

27. Gelalis ID, Politis AN, Arnaoutoglou CM, Korompilias AV, Pakos EE,

Vekris MD, Karageorgos A, Xenakis TA. Diagnostic and treatment

modalities in nonunions of the femoral shaft: a review. Injury.

2012;43(7):980-8.

28. Antonova E, Le TK, Burge R, Mershon J. Tibia shaft fractures: costly

burden of nonunions. BMC Musculoskelet Disord. 2013;14:42.

29. Schmidt AH, Finkemeier CG, Tornetta P 3rd. Treatment of closed tibial

fractures. Instr Course Lect. 2003;52:607-22.

30. Daly PJ, Fitzgerald RH Jr, Melton LJ, Ilstrup DM. Epidemiology of

ankle fractures in Rochester, Minnesota. Acta Orthop Scand.

1987;58(5):539-44.

31. Jensen SL, Andresen BK, Mencke S, Nielsen PT. Epidemiology of ankle

fractures. A prospective population-based study of 212 cases in

Aalborg, Denmark. Acta Orthop Scand. 1998;69(1):48-50.

32. SooHoo NF, Krenek L, Eagan MJ, Gurbani B, Ko Cy, zingmond DS.

Complication rates following open reduction and internal fixation of

ankle fractures. J Bone Joint Surg Am. 2009;91(5):1042-9.

33. Belatti DA, Phisitkul P. Economic burden of foot and ankle surgery in

the US Medicare population. Foot Ankle Int. 2014;35(4):334-40.

34. Henrich D, Seebach C, Sterlepper E, Tauchmann C, Marzi I, Frank J. RIA

reamings and hip aspirate: a comparative evaluation of osteoprogenitor

and endothelial progenitor cells. Injury 2010;41 Suppl 2:S62-8.

35. Schmidmaier G, Herrmann S, Green J, weber T, Scharfenberger A, Haas

NP, et al. Quantitative assessment of growth factors in reaming aspirate,

iliac crest, and platelet preparation. Bone 2006;39(5):1156–63.

36. St John TA, Vaccaro AR, Sah AP, Schaefer M, Berta SC, Albert T, et al.

Physical and monetary costs associated with autogenous bone graft

harvesting. Am J Orthop 2003;32(1):18–23.

37. Hernigou P, Poignard A, Beaujean F, Rouard H. Percutaneous

autologous bone-marrow grafting for nonunions. Influence of the

number and concentration of progenitor cells. J Bone Joint Surg Am.

2005;87(7):1430-7.

38. Grabowski G, Cornett CA. Bone graft and bone graft substitutes in

spine surgery: current concepts and controversies. J Am Acad Orthop

Surg. 2013;21(1):51-60.

39. Simmonds MC, Brown JV, Heirs MK, Higgins JP, Mannion RJ, Rodgers

MA, Stewart LA. Safety and effectiveness of recombinant human bone

morphogenetic protein-2 for spinal fusion: a meta-analysis of

individual-participant data. Ann Intern Med. 2013;158(12):877-89.

40. Fu R, Selph S, McDonagh M, Peterson K, Tiwari A, Chou R, Helfand M.

Effectiveness and harms of recombinant human bone morphogenetic

protein-2 in spine fusion: a systematic review and meta-analysis. Ann

Intern Med. 2013;158(12):890-902.

41. Kleinman S, Busch MP, Korelitz JJ, Schreiber GB. The Incidence-window

Period Model and its Use to Assess the Risk of of Transfusion-

Transmitted Human Immunodeficiency Virus and Hepatitus C Infection.

Transfusion Medicine Reviews, Vol. 11, No 3 (July), 1997: pp155-172.

42. Singh S, Blevins MB, wakeman M, Bergevin M. The Utility of Recovery

Biopsies in Determining Donor Suitability. Cell and Tissue Banking,

Vol. 13, Issue 4 (December), 2012: pp565-567.

REfERENCES


dEPUy SyNTHES TRAUMA: foCUSEd oN PATIENTS ANd HoSPITALS

Trusted Quality and Innovation

• A century of breakthroughs that create value

Delivering Solutions That Help Improve Clinical Outcomes

• Industry leader in trauma

• Provide a broad, high-quality product portfolio that addresses all your trauma needs

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• Reimbursement hotline for coding support: 1-800-895-7764 option 2

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Please refer to the instructions for use for a complete list of indications, contraindications, precautions and warnings.

For further information on DePuy Synthes Products, please contact your local DePuy Synthes Representative.

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